Benzothiepines having activity as inhibitors of ileal bile acid transport and taurocholate uptake

ABSTRACT

Provided are novel benzothiepines, derivatives, and analogs thereof; pharmaceutical compositions containing them; and methods of using these compounds and compositions in medicine, particularly in the prophylaxis and treatment of hyperlipidemic conditions such as those associated with atherosclerosis or hypercholesterolemia, in mammals.

This application is a continuation application of U.S. application Ser. No. 09/443,403, filed Nov. 19, 1999, now U.S. Pat. No. 6,262,277, which is a continuation application of U.S. application Ser. No. 09/275,463, filed Mar. 24, 1999, U.S. Pat. No. 6,107,494, which is a continuation-in-part application of U.S. application Ser. No. 09/109,551, filed Jul. 2, 1998, U.S. Pat. No. 5,994,391, which is a continuation-in-part application of U.S. application Ser. No. 08/816,065, filed Mar. 11, 1997, abandoned, which claims benefit of priority of U.S. Provisional Application Serial No. 60/013,119, filed Mar. 11, 1996, abandoned. This application is also a continuation-in-part application of U.S. application Ser. No. 08/831,284, filed Mar. 31, 1997, abandoned, which is a continuation of U.S. application Ser. No. 08/517,051, filed Aug. 21, 1995, abandoned, which is a continuation-in-part application of U.S. application Ser. No. 08/305,526, filed Sep. 13, 1994, abandoned.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to novel benzothiepines, derivatives and analogs thereof, pharmaceutical compositions containing them, and their use in medicine, particularly in the prophylaxis and treatment of hyperlipidemic conditions such as is associated with atherosclerosis or hypercholesterolemia, in mammals.

2. Description of Related Art

It is well-settled that hyperlipidemic conditions associated with elevated concentrations of total cholesterol and low-density lipoprotein cholesterol are major risk factors for coronary heart disease and particularly atherosclerosis. Interfering with the circulation of bile acids within the lumen of the intestinal tract is found to reduce the levels of serum cholesterol in a causal relationship. Epidemiological data has accumulated which indicates such reduction leads to an improvement in the disease state of atherosclerosis. Stedronsky, in “Interaction of bile acids and cholesterol with nonsystemic agents having hypocholesterolemic properties,” Biochimica et Biophysica Acta, 1210 (1994) 255-287 discusses the biochemistry, physiology and known active agents surrounding bile acids and cholesterol.

Pathophysiologic alterations are shown to be consistent with interruption of the enterohepatic circulation of bile acids in humans by Heubi, J. E., et al. See “Primary Bile Acid Malabsorption: Defective in Vitro Ileal Active Bile Acid Transport”, Gastroenterology, 1982:83:804-11.

In fact, cholestyramine binds the bile acids in the intestinal tract, thereby interfering with their normal enterohepatic circulation (Reihnér, E. et al, in “Regulation of hepatic cholesterol metabolism in humans: stimulatory effects of cholestyramine on HMG-CoA reductase activity and low density lipoprotein receptor expression in gallstone patients”, Journal of Lipid Research, Volume 31, 1990, 2219-2226 and Suckling el al, “Cholesterol Lowering and bile acid excretion in the hamster with cholestyramine treatment”, Atherosclerosis, 89(1991) 183-190). This results in an increase in liver bile acid synthesis by the liver using cholesterol as well as an upregulation of the liver LDL receptors which enhances clearance of cholesterol and decreases serum LDL cholesterol levels.

In another approach to the reduction of recirculation of bile acids, the ileal bile acid transport system is a putative pharmaceutical target for the treatment of hypercholesterolemia based on an interruption of the enterohepatic circulation with specific transport inhibitors (Kramer, et al, “Intestinal Bile Acid Absorption” The Journal of Biological Chemistry, Vol. 268, No. 24, Issue of August 25, pp. 18035-18046, 1993).

In a series of patent applications, eg Canadian Patent Application Nos. 2,025,294; 2,078,588; 2,085,782; and 2,085,830; and EP Application Nos. 0 379 161; 0 549 967; 0 559 064; and 0 563 731, Hoechst Aktiengesellschaft discloses polymers of various naturally occurring constituents of the enterohepatic circulation system and their derivatives, including bile acid, which inhibit the physiological bile acid transport with the goal of reducing the LDL cholesterol level sufficiently to be effective as pharmaceuticals and, in particular for use as hypocholesterolemic agents.

In vitro bile acid transportinhibition is disclosed to show hypolipidemic activity in The Wellcome Foundation Limited disclosure of the world patent application number WO 93/16055 for “Hypolipidemic Benzothiazepine Compounds”.

Selected benzothiepines are disclosed in world patent application number WO 93/321146 for numerous uses including fatty acid metabolism and coronary vascular diseases.

Other selected benzothiepines are known for use as hypolipaemic and hypocholesterolaemic agents, especially for the treatment or prevention of atherosclerosis as disclosed by application Nos. EP 508425, FR 2661676, and WO 92/18462, each of which is limited by an amide bonded to the carbon adjacent the phenyl ring of the fused bicyclo benzothiepine ring.

The above references show continuing efforts to find safe, effective agents for the prophylaxis and treatment of hyperlipidemic diseases and their usefulness as hypocholesterolemic agents.

Additionally selected benzothiepines are disclosed for use in various disease states not within the present invention utility. These are EP 568 898A as abstracted by Derwent Abstract No. 93-351589; WO 89/1477/A as abstracted in Derwent Abstract No. 89-370688; U.S. Pat. No. 3,520,891 abstracted in Derwent 50701R-B; U.S. Pat. Nos. 3,287,370, 3,389,144; 3,694,446 abstracted in Derwent Abstr. No. 65860T-B and WO 92/18462.

The present invention furthers such efforts by providing novel benzothiepines, pharmaceutical compositions, and methods of use therefor.

SUMMARY OF THE INVENTION

Accordingly, among its various apects, the present invention provides compounds of formula (I):

wherein:

q is an integer from 1 to 4;

n is an integer from 0 to 2;

R¹ and R² are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl,

wherein alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl optionally are substituted with one or more substituents selected from the group consisting of OR⁹, NR⁹R¹⁰, N⁺R⁹R¹⁰R^(w)A⁻, SR⁹, S⁺R⁹R¹⁰A⁻. P⁺R⁹R¹⁰R¹¹A⁻, S(O)R⁹, SO₂R⁹, SO₃R⁹, CO₂R⁹, CN, halogen, oxo, and CONR⁹R¹⁰,

wherein alkyl, alkenyl, alkynyl, alkylaryl, alkoxy, alkoxyalkyl, (polyalkyl)aryl, and cycloalkyl optionally have one or more carbons replaced by O, NR⁹, N⁺R⁹R¹⁰A—, S, SO, SO₂, S⁺R⁹A⁻, P⁺R⁹R¹⁰A⁻, or phenylene,

wherein R⁹, R¹⁰, and R^(w) are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, arylalkyl, carboxyalkyl, carboxyheteroaryl, carboxyheterocycle, carboalkoxalkyl, carboxyalkylamino, heteroarylalkyl, heterocyclylalkyl, and alkylammoniumalkyl; or

R¹ and R² taken together with the carbon to which they are attached form C₃-C₁₀ cycloalkyl;

R³ and R⁴ are independently selected from the group consisting of H, alkyl, alkenyl, acyloxy, aryl, heterocycle, OR⁹, NR⁹R¹⁰, SR⁹, S(O)R⁹, SO₂R⁹, and SO₃R⁹, wherein R⁹ and R¹⁰ are as defined above; or

R³ and R⁴ together form ═O, ═NOR¹¹, ═S, ═NNR¹¹R¹², ═NR⁹, or ═CR¹¹R¹²,

wherein R¹¹ and R¹² are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl, OR⁹, NR⁹R¹⁰, SR⁹, S(O)R⁹, SO₂R⁹, SO₃R⁹, CO₂R⁹, CN, halogen, oxo, and CONR⁹R¹⁰, wherein R⁹ and R¹⁰ are as defined above, provided that both R³ and R⁴ cannot be OH, NH₂, and SH, or

R¹¹ and R¹² together with the nitrogen or carbon atom to which they are attached form a cyclic ring;

R⁵ and R⁶ are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, OR⁹, SR⁹, S(O)R⁹, SO₂R⁹, and SO₃R⁹,

wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, and quaternary heteroaryl can be substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, halogen, oxo, OR¹³, NR¹³R¹⁴, SR¹³, S(O)R¹³, SO₂R¹³, SO₃R¹³, NR¹³OR¹⁴, NR¹³NR¹⁴R¹⁵, NO₂, CO₂R¹³, CN OM, SO₂OM, SO₂NR¹³R¹⁴, C(O)NR¹³R¹⁴, C(O)OM, COR¹³, NR¹³C(O)R¹⁴, NR¹³C(O)NR¹⁴R¹⁵, NR¹³CO₂R¹⁴, OC(O)R¹³, OC(O)NR¹³R¹⁴, NR¹³SOR¹⁴, NR¹³SO₂R¹⁴, NR¹³SONR¹⁴R¹⁵, NR¹³SO₂NR¹⁴R¹⁵, P(O)R¹³R¹⁴, P⁺R¹³R¹⁴R¹⁵A⁻, P(OR¹³)OR¹⁴, S⁺R¹³R¹⁴A⁻, and N⁺R⁹R¹¹R¹²A⁻,

wherein:

A⁻ is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation,

said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can be further substituted with one or more substituent groups selected from the group consisting of OR⁷, NR⁷R⁸, SR⁷, S(O)R⁷, SO₂R⁷, SO₃R⁷, CO₂R⁷, CN, oxo, CONR⁷R⁸, N⁺R⁷R⁸R⁹A—, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, P(O)R⁷R⁸, P⁺R⁷R⁸R⁹A⁻, and P(O)(OR⁷)OR⁸, and

wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can optionally have one or more carbons replaced by O, NR⁷, N⁺R⁷R⁸A—, S, SO, SO₂, S⁺R⁷A—, PR⁷, P(O)R⁷, P⁺R⁷R⁸A—, or phenylene, and R¹³, R¹⁴, and R¹⁵ are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, arylalkyl, alkylarylalkyl, alkylheteroarylalkyl, alkylheterocyclylalkyl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, heterocyclylalkyl, heteroarylalkyl, quaternary heterocyclylalkyl, quaternary heteroarylalkyl, alkylammoniumalkyl, and carboxyalkylaminocarbonylalkyl,

wherein alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, and polyalkyl optionally have one or more carbons replaced by O, NR⁹, N⁺R⁹R¹⁰A—, S, SO, SO₂, S⁺R⁹A⁻, PR⁹, P⁺R⁹R¹⁰A—, P(O)R⁹, phenylene, carbohydrate, amino acid, peptide, or polypeptide, and

R¹³, R¹⁴, and R¹⁵ are optionally substituted with one or more groups selected from the group consisting of hydroxy, amino, sulfo, carboxy, alkyl, carboxyalkyl, heterocycle, heteroaryl, sulfoalkyl, quaternary heterocycle, quaternary heteroaryl, quaternary heterocyclylalkyl, quaternary heteroarylalkyl, guanidinyl, OR⁹, NR⁹R¹⁰, N⁺R⁹R¹¹R¹²A⁻, SR⁹, S(O)R⁹, SO₂R⁹, SO₃R⁹, oxo, CO₂R⁹, CN, halogen, CONR⁹R¹⁰, SO₂OM, SO₂NR⁹R¹⁰, PO(OR¹⁶)OR¹⁷, P³⁰ R⁹R¹⁰R¹¹A—, S⁺R⁹R¹⁰A—, and C(O)OM,

wherein R¹⁶ and R¹⁷ are independently selected from the substituents constituting R⁹ and M; or

R¹³ and R¹⁴, together with the nitrogen atom to which they are attached form a mono- or polycyclic heterocycle that is optionally substituted with one or more radicals selected from the group consisting of oxo, carboxy and quaternary salts; or

R¹⁴ and R¹⁵, together with the nitrogen atom to which they are attached, form a cyclic ring; and

R⁷ and R⁸ are independently selected from the group consisting of hydrogen and alkyl; and

one or more R^(x) are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, polyalkyl, acyloxy, aryl, arylalkyl, halogen, haloalkyl, cycloalkyl, heterocycle, heteroaryl, polyether, quaternary heterocycle, quaternary heteroaryl, OR¹³, NR¹³R¹⁴, SR¹³, S(O)R¹³, S(O)₂R¹³, SO₃R¹³, S⁺R¹³R¹⁴A—, NR¹³OR¹⁴, NR¹³NR¹⁴R¹⁵, NO₂, CO₂R¹³, CN, OM, SO₂OM, SO₂NR¹³R¹⁴, NR¹⁴C(O)R¹³, C(O)NR¹³R¹⁴, NR¹⁴C(O)R¹³, C(O)OM, COR¹³, OR¹⁸, S(O)_(n)NR¹⁸, NR¹³R¹⁸, NR¹⁸OR¹⁴, N⁺R⁹R¹¹R¹²A⁻, P⁺R⁹R¹¹R¹²A⁻, amino acid, peptide, polypeptide, and carbohydrate,

wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, polyalkyl, heterocycle, acyloxy, arylalkyl, haloalkyl, polyether, quaternary heterocycle, and quaternary heteroaryl can be further substituted with OR⁹, NR⁹R¹⁰, N⁺R⁹R¹¹R¹²A⁻, SR⁹, S(O)R⁹, SO₂R⁹, SO₃R⁹, oxo, CO₂R⁹, CN, halogen, CONR⁹R¹⁰, SO₂OM, SO₂NR⁹R¹⁰, PO(OR¹⁶)OR¹⁷, p⁺R⁹R¹¹R¹²A⁻, S⁺R⁹R¹⁰A⁻, or C(O)OM, and

wherein R¹⁸ is selected from the group consisting of acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl,

wherein acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, quaternary heterocycle, and quaternary heteroaryl optionally are substituted with one or more substituents selected from the group consisting of OR⁹, NR⁹R¹⁰, N⁺R⁹R¹¹R¹²A⁻, SR⁹, S(O)R⁹, SO₂R⁹, SO₃R⁹, oxo, CO₂R⁹, CN, halogen, CONR⁹R¹⁰, SO₃R⁹, SO₂OM, SO₂NR⁹R¹⁰, PO(OR¹⁶)OR¹⁷, and C(O)M,

wherein in R^(x), one or more carbons are optionally replaced by O, NR¹³, N⁺R¹³R¹⁴A—, S, SO, SO₂, S⁺R¹³A⁻, PR¹³, P(O)R¹³, P⁺R¹³R¹⁴A—, phenylene, amino acid, peptide, polypeptide, carbohydrate, polyether, or polyalkyl,

wherein in said polyalkyl, phenylene, amino acid, peptide, polypeptide, and carbohydrate, one or more carbons are optionally replaced by O, NR⁹, N⁺R⁹R¹⁰A⁻, S, SO, SO₂, S⁺R⁹A—, PR⁹, P⁺R⁹R¹⁰A—, or P(O)R⁹;

wherein quaternary heterocycle and quaternary heteroaryl are optionally substituted with one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR¹³, NR¹³R¹⁴, SR¹³, S(O)R¹³, SO₂R¹³, SO₃R¹³, NR¹³OR¹⁴, NR¹³NR¹⁴R¹⁵, NO₂, CO₂R¹³, CN, OM, SO₂OM, SO₂NR¹³R¹⁴, C(O)NR¹³R¹⁴, C(O)OM, COR¹³, P(O)R¹³R¹⁴, P⁺R¹³R¹⁴R¹⁵A⁻, P(OR¹³)OR¹⁴, S⁺R¹³R¹⁴A⁻, and N⁺R⁹R¹¹R¹²A⁻,

provided that both R⁵ and R⁶ cannot be hydrogen, OH, or SH and when R⁵ is OH, R¹, R², R³, R⁴, R⁷ and R⁸ cannot be all hydrogen;

provided that when R⁵ or R⁶ is phenyl, only one of R¹ or R² is H;

provided that when q=1 and R^(x) is styryl, anilido, or anilinocarbonyl, only one of R⁵ or R⁶ is alkyl;

provided that when n is 1, R¹, R³, R⁷, and R⁸ are hydrogen, R² is hydrogen, alkyl or aryl, R⁴ is unsubstituted amino or amino substituted with one or more alkyl or aryl radicals, and R⁵ is hydrogen, alkyl or aryl, then R⁶ is other than hydroxy; or

a pharmaceutically acceptable salt, solvate, or prodrug thereof.

Preferably, R⁵ and R⁶ can independently be selected from the group consisting of H, aryl, heterocycle, quaternary heterocycle, and quaternary heteroaryl,

wherein said aryl, heteroaryl, quaternary heterocycle, and quaternary heteroaryl can be substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR¹³, NR¹³R¹⁴, SR¹³, S(O)R¹³, SO₂R¹³, SO₃R¹³, NR¹³OR¹⁴, NR¹³NR¹⁴R¹⁵, NO₂, CO₂R¹³, CN, OM, SO₂OM, SO₂NR¹³R¹⁴, C(O)NR¹³R¹⁴, C(O)OM, COR¹³, NR¹³C(O)R¹⁴, NR¹³C(O)NR¹⁴R¹⁵, NR¹³CO₂R¹⁴, OC(O)R¹³, OC(O)NR¹³R¹⁴, NR¹³SOR¹⁴, NR¹³SO₂R¹⁴, NR¹³SONR¹⁴R¹⁵, NR¹³SO₂NR¹⁴R¹⁵, P(O)R¹³R¹⁴, P⁺R¹³R¹⁴R15A—, P(OR¹³)OR¹⁴, S+R¹³R¹⁴A—, and N⁺R⁹R¹¹R¹²A⁻,

wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can optionally have one or more carbons replaced by O, NR⁷, N⁺R⁷R⁸A—, S, SO, SO₂, S⁺R⁷A—, PR⁷, P(O)R⁷, P⁺R⁷R⁸A—, or phenylene,

wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can be further substituted with one or more substituent groups selected from the group consisting of OR⁷, NR⁷R⁸, SR⁷, S(O)R⁷, SO₂R⁷, SO₃R⁷, CO₂R⁷, CN, oxo, CONR⁷R⁸, N⁺R⁷R⁸R⁹A⁻, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, P(O)R⁷R⁸, P⁺R⁷R⁸A⁻, and P(O)(OR⁷)OR⁸.

More preferably, R⁵ or R⁶ has the formula:

wherein:

t is an integer from 0 to 5;

Ar is selected from the group consisting of phenyl, thiophenyl, pyridyl, piperazinyl, piperonyl, pyrrolyl, naphthyl, furanyl, anthracenyl, quinolinyl, isoquinolinyl, quinoxalinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrimidinyl, thiazolyl, triazolyl, isothiazolyl, indolyl, benzoimidazolyl, benzoxazolyl, benzothiazolyl, and benzoisothiazolyl; and

one or more R^(y) are independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR¹³, NR¹³R¹⁴, SR¹³, S(O)R¹³, SO₂R¹³, SO₃R¹³, NR¹³OR¹⁴, NR¹³NR¹⁴R¹⁵, NO₂, CO₂R¹³, CN OM, SO₂OM, SO₂NR¹³R¹⁴, C(O)N¹³R¹⁴, C(O)M, COR¹³, NR¹³C(O)R¹⁴, NR¹³C(O)NR¹⁴R¹⁵, NR¹³CO₂R¹⁴, OC(O)R¹³, OC(O)NR¹³R¹⁴, NR¹³SOR¹⁴, NR¹³SO₂R¹⁴, NR¹³SONR¹⁴R¹⁵, NR¹³SO₂NR¹⁴R¹⁵, P(O)R¹³R¹⁴, P⁺R¹³R¹⁴R¹⁵A⁻, P(OR¹³)OR¹⁴, S⁺R¹³R¹⁴A⁻, and N⁺R⁹R¹¹R¹²A⁻,

wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can be further substituted with one or more substituent groups selected from the group consisting of OR⁷, NR⁷R⁸, SR⁷, S(O)R⁷, SO₂R⁷, SO₃R⁷, CO₂R⁷, CN, oxo, CONR⁷R⁸, N⁺R⁷R⁸R⁹A—, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, P(O)R⁷R⁸, P⁺R⁷R⁸A⁻, and P(O)(OR⁷)OR⁸, and

wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can optionally have one or more carbons replaced by O, NR⁷, N⁺R⁷R⁸A—, S, SO, SO₂, S⁺R⁷A—, PR⁷, P(O)R⁷, P⁺R⁷R⁸A—, or phenylene.

Most preferably, R⁵ or R⁶ has the formula (II):

Another embodiment of the invention is further directed to compounds of Formula I wherein at least one or more of the following conditions exist:

(1) R¹ and R² are independently selected from the group consisting of hydrogen and alkyl. Preferably, R¹ and R² are independently selected from the group consisting of C₁₋₆ alkyl. More preferably, R¹ and R² are the same C₁₋₆ alkyl. Still more preferably, R¹ and R² are n-butyl; and/or

(2) R³ and R⁴ are independently selected from the group consisting of hydrogen and OR⁹ wherein R⁹ is defined as set forth above. Preferably, R³ is hydrogen and R⁴ is OR⁹. Still more preferably, R³ is hydrogen and R⁴ is hydroxy; and/or

(3) R⁵ is substituted aryl. Preferably, R⁵ is substituted phenyl. More preferably, R⁵ is phenyl substituted with a radical selected from the group consisting of OR¹³, NR¹³C(O)R¹⁴, NR¹³C(O)NR¹⁴R¹⁵, NR¹³CO₂R¹⁴, OC(O)R¹³, OC(O)NR¹³R¹⁴, NR¹³SOR¹⁴, NR¹³SO₂R¹⁴, NR¹³SONR¹⁴R¹⁵, and NR¹³SO₂NR¹⁴R¹⁵ wherein R¹³, R¹⁴ and R¹⁵ are as set forth above. Still more preferably, R⁵ is phenyl substituted with OR¹³. Still more preferably, R⁵ is phenyl substituted at the para or meta position with OR¹³ wherein R¹³ comprises a quaternary heterocycle, quaternary heteroaryl or substituted amino; and/or

(4) R⁶ is hydrogen; and/or

(5) R⁷ and R⁸ are independently selected from the group consisting of hydrogen and alkyl. Preferably, R¹ and R² are independently selected from the group C₁₋₆ alkyl. Still more preferably, R¹ and R² are hydrogen; and/or

(6) R^(x) is selected from the group consisting of OR¹³ and NR¹³R¹⁴. Preferably, R^(x) is selected from the group consisting of alkoxy, amino, alkylamino and dialkylamino. Still more preferably, R^(x) is selected from the group consisting of methoxy and dimethylamino.

Another embodiment of the invention is further directed to compounds of formula 1:

wherein:

q is an integer from 1 to 4;

n is an integer from 0 to 2;

R¹ and R² are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl,

wherein alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl optionally are substituted with one or more substituents selected from the group consisting of OR⁹, NR⁹R¹⁰, N⁺R⁹R¹⁰R^(w)A⁻, SR⁹, S⁺R⁹R¹⁰A⁻. P^(+R) ⁹R¹⁰R¹¹A⁻, S(O)R⁹, SO₂R⁹, SO₃R⁹, CO₂R⁹, CN, halogen, oxo, and CONR⁹R¹⁰,

wherein alkyl, alkenyl, alkynyl, alkylaryl, alkoxy, alkoxyalkyl, (polyalkyl)aryl, and cycloalkyl optionally have one or more carbons replaced by O, NR⁹, N⁺R⁹R¹⁰A—, S, SO, S₂, S⁺R⁹A⁻, P⁺R⁹R¹⁰A⁻, or phenylene,

wherein R⁹, R¹⁰, and R^(w) are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, arylalkyl, carboxyalkyl, carboxyheteroaryl, carboxyheterocycle, carboalkoxyalkyl, carboxyalkylamino, heteroarylalkyl, heterocyclylalkyl, and alkylammoniumalkyl; or

R¹ and R² taken together with the carbon to which they are attached form C₃-C₁₀ cycloalkyl;

R³ and R⁴ are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, acyloxy, aryl, heterocycle, OR⁹, SR⁹, S(O)R⁹, SO₂R⁹, and SO₃R⁹, wherein R⁹ and R¹⁰ are as defined above; or

R³ and R⁴ together form ═O, ═NOR¹¹, ═S, ═NNR¹¹R¹², ═NR⁹, or ═CR¹¹R¹²,

wherein R¹¹ and R¹² are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl, OR⁹, NR⁹R¹⁰, SR⁹, S(O)R⁹, SO₂R⁹, SO₃R⁹, CO₂R⁹, CN, halogen, oxo, and CONR⁹R¹⁰, wherein R⁹ and R¹⁰ are as defined above, provided that both R³ and R⁴ cannot be OH, NH₂, and SH, or

R¹¹ and R¹² together with the nitrogen or carbon atom to which they are attached form a cyclic ring;

R⁵ is selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, OR⁹, SR⁹, S(O)R⁹, SO₂R⁹, and SO₃R⁹,

wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, and quaternary heteroaryl can be substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, halogen, oxo, OR¹³, NR¹³R¹⁴, SR¹³, S(O)R¹³, SO₂R¹³, SO₃R¹³, NR¹³OR¹⁴, NR¹³NR¹⁴R¹⁵, NO₂, CO₂R¹³, CN, OM, SO₂OM, SO₂NR¹³R¹⁴, C(O)NR¹³R¹⁴, C(O)OM, COR¹³, NR¹³C(O)R¹⁴, NR¹³C(O)NR¹⁴R¹⁵, NR¹³CO₂R¹⁴, OC(O)R¹³, OC(O)NR¹³R¹⁴, NR¹³SOR¹⁴, NR¹³SO₂R¹⁴, NR¹³SONR¹⁴R¹⁵, NR¹³SO₂NR¹⁴R¹⁵, P(O)R¹³R¹⁴, p⁺R¹³R¹⁴R¹⁵A⁻, P(OR¹³)OR¹⁴, S⁺R¹³R¹⁴A⁻, and N⁺R⁹R¹¹R¹²A⁻,

wherein:

A⁻ is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation,

said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can be further substituted with one or more substituent groups selected from the group consisting of OR⁷, NR⁷R⁸, SR⁷, S(O)R⁷, SO₂R⁷, SO₃R⁷, CO₂R⁷, CN, oxo, CONR⁷R⁸, N⁺R⁷R⁸R⁹A—, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, P(O)R⁷R⁸, P⁺R⁷R⁸R⁹A⁻, and P(O)(OR⁷)OR⁸, and

wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can optionally have one or more carbons replaced by O, NR⁷, N⁺R⁷R⁸A—, S, SO, SO₂, S⁺R⁷A—, PR⁷, P(O)R⁷, P⁺R⁷R⁸A—, or phenylene, and R¹³, R¹⁴, and R¹⁵ are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, arylalkyl, alkylarylalkyl, alkylheteroarylalkyl, alkylheterocyclylalkyl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, heterocyclylalkyl, heteroarylalkyl, quaternary heterocyclylalkyl, quaternary heteroarylalkyl, alkylammoniumalkyl, and carboxyalkylaminocarbonylalkyl,

wherein alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, and polyalkyl optionally have one or more carbons replaced by O, NR⁹, N⁺R⁹R¹⁰A—, S, SO, SO₂, S⁺R⁹A⁻, PR⁹, P⁺R⁹R¹⁰A—, P(O)R⁹, phenylene, carbohydrate, amino acid, peptide, or polypeptide, and

R¹³, R¹⁴, and R¹⁵ are optionally substituted with one or more groups selected from the group consisting of hydroxy, amino, sulfo, carboxy, alkyl, carboxyalkyl, heterocycle, heteroaryl, sulfoalkyl, quaternary heterocycle, quaternary heteroaryl, quaternary heterocyclylalkyl, quaternary heteroarylalkyl, guanidinyl, OR⁹, NR⁹R¹⁰, N⁺R⁹R¹¹R¹²A⁻, SR⁹, S(O)R⁹, SO₂R⁹, SO₃R⁹, oxo, CO₂R⁹, CN, halogen, CONR⁹R¹⁰, SO₂OM, SO₂NR⁹R¹⁰, PO(OR¹⁶)OR¹⁷, P⁺R⁹R¹⁰R¹¹A—, S⁺R⁹R¹⁰A—, and C(O)OM,

wherein R¹⁶ and R¹⁷ are independently selected from the substituents constituting R⁹ and M; or

R¹³ and R¹⁴, together with the nitrogen atom to which they are attached form a mono- or polycyclic heterocycle that is optionally substituted with one or more radicals selected from the group consisting of oxo, carboxy and quaternary salts; or

R¹⁴ and R¹⁵, together with the nitrogen atom to which they are attached, form a cyclic ring; and

R⁶ is hydroxy; and

R⁷ and R⁸ are independently selected from the group consisting of hydrogen and alkyl; and

one or more R^(x) are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, polyalkyl, acyloxy, aryl, arylalkyl, halogen, haloalkyl, cycloalkyl, heterocycle, heteroaryl, polyether, quaternary heterocycle, quaternary heteroaryl, OR¹³, NR¹³R¹⁴, SR¹³, S(O)R¹³, S(O)₂R¹³, SO₃R¹³, S⁺R¹³R¹⁴A—, NR¹³OR¹⁴, NR¹³NR¹⁴R¹⁵, NO₂, CO₂R¹³, CN, OM, SO₂OM, SO₂NR¹³R¹⁴, NR¹⁴C(O)R¹³, C(O)NR¹³R¹⁴, NR¹⁴C(O)R¹³, C(O)OM, COR¹³, OR¹⁸, S(O)_(n)NR¹⁸, NR¹³R¹⁸, NR¹⁸OR¹⁴, N⁺R⁹R¹¹R¹²A⁻, P⁺R⁹R¹¹R¹²A⁻, amino acid, peptide, polypeptide, and carbohydrate,

wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, polyalkyl, heterocycle, acyloxy, arylalkyl, haloalkyl, polyether, quaternary heterocycle, and quaternary heteroaryl can be further substituted with OR⁹, NR⁹R¹⁰, N⁺R⁹R¹¹R¹²A⁻, SR⁹, S(O)R⁹, SO₂R⁹, SO₃R⁹, oxo, CO₂R⁹, CN, halogen, CONR⁹R¹⁰, SO₂OM, SO₂NR⁹R¹⁰, PO(OR¹⁶)OR¹⁷, P⁺R⁹R¹¹R¹²A⁻, S⁺R⁹R¹⁰A⁻, or C(O)OM, and

wherein R¹⁸ is selected from the group consisting of acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl,

wherein acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, quaternary heterocycle, and quaternary heteroaryl optionally are substituted with one or more substituents selected from the group consisting of OR⁹, NR⁹R¹⁰, N⁺R⁹R¹¹R¹²A⁻, SR⁹, S(O)R⁹, SO₂R⁹, SO₃R⁹, oxo, CO₂R⁹, CN, halogen, CONR⁹R¹⁰, SO₃R⁹, SO₂OM, SO₂NR⁹R¹⁰, PO(OR¹⁶)OR¹⁷, and C(O)OM,

wherein in R^(x), one or more carbons are optionally replaced by O, NR¹³, N⁺R¹³R¹⁴A—, S, SO, SO₂, S⁺R¹³A⁻, PR¹³, P(O)R¹³, P⁺R¹³R¹⁴A—, phenylene, amino acid, peptide, polypeptide, carbohydrate, polyether, or polyalkyl,

wherein in said polyalkyl, phenylene, amino acid, peptide, polypeptide, and carbohydrate, one or more carbons are optionally replaced by O, NR⁹, N⁺R⁹R¹⁰A⁻, S, SO, SO₂, S⁺R⁹A—, PR⁹, P⁺R⁹R¹⁰A—, or P(O)R⁹;

wherein quaternary heterocycle and quaternary heteroaryl are optionally substituted with one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, R¹³, NR¹³R¹⁴, SR¹³, S(O)R¹³, SO₂R¹³, SO₃R¹³, NR¹³OR¹⁴, NR¹³NR¹⁴R¹⁵, NO₂, CO₂R¹³, CN, OM, SO₂OM, SO₂NR¹³R¹⁴, C(O)NR¹³R¹⁴, C(O)OM, COR¹³, P(O)R¹³R¹⁴, P⁺R¹³R¹⁴R¹⁵A⁻, P(OR¹³)OR¹⁴, S⁺R¹³R¹⁴A⁻, and N⁺R⁹R¹¹R¹²A⁻,

provided that both R⁵ and R⁶ cannot be hydrogen, OH, or SH;

provided that when R⁵ is phenyl, only one of R¹ or R² is H; or

a pharmaceutically acceptable salt, solvate, or prodrug thereof.

The invention is further directed to a compound selected from among:

R²⁰—R¹⁹—R²¹  (Formula DI)

 R²³

wherein

R¹⁹ is selected from the group consisting of alkane diyl, alkene diyl, alkyne diyl, polyalkane diyl, alkoxy diyl, polyether diyl, polyalkoxy diyl, carbohydrate, amino acid, peptide, and polypeptide, wherein alkane diyl, alkene diyl, alkyne diyl, polyalkane diyl, alkoxy diyl, polyether diyl, polyalkoxy diyl, carbohydrate, amino acid, peptide, and polypeptide can optionally have one or more carbon atoms replaced by O, NR⁷, N⁺R⁷R⁸, S, SO, SO₂, S⁺R⁷R⁸, PR⁷, P⁺R⁷R⁸, phenylene, heterocycle, quatarnary heterocycle, quaternary heteroaryl, or aryl,

wherein alkane diyl, alkene diyl, alkyne diyl, polyalkane diyl, alkoxy diyl, polyether diyl, polyalkoxy diyl, carbohydrate, amino acid, peptide, and polypeptide can be substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR¹³, NR¹³R¹⁴, SR¹³, S(O)R¹³, SO₂R¹³, SO₃R¹³, NR¹³OR¹⁴, NR¹³NR¹⁴R¹⁵, NO₂, CO₂R¹³, CN, OM, SO₂OM, SO₂NR¹³R¹⁴, C(O)NR¹³R¹⁴, C(O)OM, COR¹³, P(O)R¹³R¹⁴, P⁺R¹³R¹⁴R15A—, P(OR¹³)OR¹⁴, S⁺R¹³R¹⁴A⁻, and N⁺R⁹R¹¹R¹²A⁻;

wherein R¹⁹ further comprises functional linkages by which R¹⁹ is bonded to R²⁰, R²¹, or R²² in the compounds of Formulae DII and DIII, and R²³ in the compounds of Formula DIII. Each of R²⁰, R²¹, or R²² and R²³ comprises a benzothiepine moiety as described above that is therapeutically effective in inhibiting ileal bile acid transport.

The invention is also directed to a compound selected from among Formula DI, Formula DII and Formula DIII in which each of R²⁰, R²¹, R²² and R²³ comprises a benzothiepine moiety corresponding to the Formula:

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R^(x), q, and n are as defined in Formula I as described above, and R⁵⁵ is either a covalent bond or arylene.

In compounds of Formula DIV, it is particularly preferred that each of R²⁰, R²¹, and R²² in Formulae DII and DIII, and R²³ in Formula DIII, be bonded at its 7- or 8-position to R¹⁹. In compounds of Formula DIVA, it is particularly preferred that R⁵⁵ comprise a phenylene moiety bonded at a m- or p-carbon thereof to R¹⁹.

Examples of Formula DI include:

In any of the dimeric or multimeric structures discussed immediately above, benzothiepine compounds of the present invention can be used alone or in various combinations.

In any of the compounds of the present invention, R¹ and R² can be ethyl/butyl or butyl/butyl.

In another aspect, the present invention provides a pharmaceutical composition for the prophylaxis or treatment of a disease or condition for which a bile acid transport inhibitor is indicated, such as a hyperlipidemic condition, for example, atherosclerosis. Such compositions comprise any of the compounds disclosed above, alone or in combination, in an amount effective to reduce bile acid levels in the blood, or to reduce transport thereof across digestive system membranes, and a pharmaceutically acceptable carrier, excipient, or diluent.

In a further aspect, the present invention also provides a method of treating a disease or condition in mammals, including humans, for which a bile acid transport inhibitor is indicated, comprising administering to a patient in need thereof a compound of the present invention in an effective amount in unit dosage form or in divided doses.

In yet a further aspect, the present invention also provides processes for the preparation of compounds of the present invention.

Further scope of the applicability of the present invention will become apparent from the detailed description provided below. However, it should be understood that the following detailed dscription and examples, while indicating preferred embodiments of the invention, are given by way of illustration only since various changes and modifications within the spirit and scope of the invention will beomce apparent to those skilled in the art from this detailed description.

DETAILED DESCRIPTION OF THE INVENTION

The following detailed description is provided to aid those skilled in the art in practicing the present invention. Even so, this detailed description should not be construed to unduly limit the present invention as modifications and variations in the emobodiments discussed herein can be made by those of ordinary skill in the art without departing from the spirit or scope of the present inventive discovery.

The contents of each of the references cited herein, including the contents of the references cited within these primary references, are herein incorporated by reference in their entirety.

Definitions

In order to aid the reader in understanding the following detailed description, the following definitions are provided:

“Alkyl”, “alkenyl,” and “alkynyl” unless otherwise noted are each straight chain or branched chain hydrocarbons of from one to twenty carbons for alkyl or two to twenty carbons for alkenyl and alkynyl in the present invention and therefore mean, for example, methyl, ethyl, propyl, butyl, pentyl or hexyl and ethenyl, propenyl, butenyl, pentenyl, or hexenyl and ethynyl, propynyl, butynyl, pentynyl, or hexynyl respectively and isomers thereof.

“Aryl” means a fully unsaturated mono- or multi-ring carbocyle, including, but not limited to, substituted or unsubstituted phenyl, naphthyl, or anthracenyl.

“Heterocycle” means a saturated or unsaturated mono- or multi-ring carbocycle wherein one or more carbon atoms can be replaced by N, S, P, or O. This includes, for example, the following structures:

wherein Z, Z′, Z″ or Z″′ is C, S, P, O, or N, with the proviso that one of Z, Z′, Z″ or Z″′ is other than carbon, but is not O or S when attached to another Z atom by a double bond or when attached to another O or S atom. Furthermore, the optional substituents are understood to be attached to Z, Z′, Z″ or Z″′ only when each is C.

The term “heteroaryl” means a fully unsaturated heterocycle.

In either “heterocycle” or “heteroaryl,” the point of attachment to the molecule of interest can be at the heteroatom or elsewhere within the ring.

The term “quaternary heterocycle” means a heterocycle in which one or more of the heteroatoms, for example, O, N, S, or P, has such a number of bonds that it is positively charged. The point of attachment of the quaternary heterocycle to the molecule of interest can be at a heteroatom or elsewhere.

The term “quaternary heteroaryl” means a heteroaryl in which one or more of the heteroatoms, for example, O, N, S, or P, has such a number of bonds that it is positively charged. The point of attachment of the quaternary heteryaryl to the molecule of interest can be at a heteroatom or elsewhere.

The term “halogen” means a fluoro, chloro, bromo or iodo group.

The term “haloalkyl” means alkyl substituted with one or more halogens.

The term “cycloalkyl” means a mono- or multi-ringed carbocycle wherein each ring contains three to ten carbon atoms, and wherein any ring can contain one or more double or triple bonds. Examples include radicals such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloalkenyl, and cycloheptyl. The term “cycloalkyl” additionally encompasses spiro systems wherein the cycloalkyl ring has a carbon ring atom in common with the seven-membered heterocyclic ring of the benzothiepine.

The term “diyl” means a diradical moiety wherein said moiety has two points of attachment to molecules of interest.

The term “oxo” means a doubly bonded oxygen.

The term “polyalkyl” means a branched or straight hydrocarbon chain having a molecular weight up to about 20,000, more preferably up to about 10,000, most preferably up to about 5,000.

The term “polyether” means a polyalkyl wherein one or more carbons are replaced by oxygen, wherein the polyether has a molecular weight up to about 20,000, more preferably up to about 10,000, most preferably up to about 5,000.

The term “polyalkoxy” means a polymer of alkylene oxides, wherein the polyalkoxy has a molecular weight up to about 20,000, more preferably up to about 10,000, most preferably up to about 5,000.

The term “cycloaklylidene” means a mono- or multi-ringed carbocycle wherein a carbon within the ring structure is doubly bonded to an atom which is not within the ring structures.

The term “carbohydrate” means a mono-, di-, tri-, or polysaccharide wherein the polysaccharide can have a molecular weight of up to about 20,000, for example, hydroxypropyl-methylcellulose or chitosan.

The term “peptide” means polyamino acid containing up to about 100 amino acid units.

The term “polypeptide” means polyamino acid containing from about 100 amino acid units to about 1000 amino acid units, more preferably from about 100 amino acid units to about 750 amino acid untis, most preferably from about 100 amino acid units to about 500 amino acid units.

The term “alkylammoniumalkyl” means a NH₂ group or a mono-, di- or tri-substituted amino group, any of which is bonded to an alkyl wherein said alkyl is bonded to the molecule of interest.

The term “triazolyl” includes all positional isomers. In all other heterocycles and heteroaryls which contain more than one ring heteroatom and for which isomers are possible, such isomers are included in the definition of said heterocycles and heteroaryls.

The term “sulfo” means a sulfo group, —SO₃H, or its salts.

The term “sulfoalkyl” means an alkyl group to which a sulfonate group is bonded, wherein said alkyl is bonded to the molecule of interest.

The term “arylalkyl” means an aryl-substituted alkyl radical such as benzyl. The term “alkylarylalkyl” means an arylalkyl radical that is substituted on the aryl group with one or more alkyl groups.

The term “heterocyclylalkyl” means an alkyl radical that is substituted with one or more heterocycle groups. Preferable heterocyclylalkyl radicals are “lower heterocyclylalkyl” radicals having one or more heterocycle groups attached to an alkyl radical having one to ten carbon atoms.

The term “heteroarylalkyl” means an alkyl radical that is substituted with one or more heteroaryl groups. Preferable heteroarylalkyl radicals are “lower heteroarylalkyl” radicals having one or more heteroaryl groups attached to an alkyl radical having one to ten carbon atoms.

The term “quaternary heterocyclylalkyl” means an alkyl radical that is substituted with one or more quaternary heterocycle groups. Preferable quaternary heterocyclylalkyl radicals are “lower quaternary heterocyclylalkyl” radicals having one or more quaternary heterocycle groups attached to an alkyl radical having one to ten carbon atoms.

The term “quaternary heteroarylalkyl” means an alkyl radical that is substituted with one or more quaternary heteroaryl groups. Preferable quaternary heteroarylalkyl radicals are “lower quaternary heteroarylalkyl” radicals having one or more quaternary heteroaryl groups attached to an alkyl radical having one to ten carbon atoms.

The term “alkylheteroarylalkyl” means a heteroarylalkyl radical that is substituted with one or more alkyl groups. Preferable alkylheteroarylalkyl radicals are “lower alkylheteroarylalkyl” radicals with alkyl portions having one to ten carbon atoms.

The term “alkoxy” an alkyl radical which is attached to the remainder of the molecule by oxygen, such as a methoxy radical. More preferred alkoxy radicals are “lower alkoxy” radicals having one to six carbon atoms. Examples of such radicals include methoxy, ethoxy, propoxy, iso-propoxy, butoxy and tert-butoxy.

The term “carboxy” means the carboxy group, —CO₂H, or its salts.

The term “carboxyalkyl” means an alkyl radical that is substituted with one or more carboxy groups. Preferable carboxyalkyl radicals are “lower carboxyalkyl” radicals having one or more carboxy groups attached to an alkyl radical having one to six carbon atoms.

The term “carboxyheterocycle” means a heterocycle radical that is substituted with one or more carboxy groups.

The term “carboxyheteroaryl” means a heteroaryl radical that is substituted with one or more carboxy groups.

The term “carboalkoxyalkyl” means an alkyl radical that is substituted with one or more alkoxycarbonyl groups. Preferable carboalkoxyalkyl radicals are “lower carboalkoxyalkyl” radicals having one or more alkoxycarbonyl groups attached to an alkyl radical having one to six carbon atoms.

The term “carboxyalkylamino” means an amino radical that is mono- or di-substituted with carboxyalkyl. Preferably, the carboxyalkyl substituent is a “lower carboxyalkyl” radical wherein the carboxy group is attached to an alkyl radical having one to six carbon atoms.

The term “active compound” means a compound of the present invention which inhibits transport of bile acids.

When used in combination, for example “alkylaryl” or “arylalkyl,” the individual terms listed above have the meaning indicated above.

The term “a bile acid transport inhibitor” means a compound capable of inhibiting absorption of bile acids from the intestine into the circulatory system of a mammal, such as a human. This includes increasing the fecal excretion of bile acids, as well as reducing the blood plasma or serum concentrations of cholesterol and cholesterol ester, and more specifically, reducing LDL and VLDL cholesterol. Conditions or diseases which benefit from the prophylaxis or treatment by bile acid transport inhibition include, for example, a hyperlipidemic condition such as atherosclerosis.

Compounds

The compounds of the present invention can have at least two asymmetrical carbon atoms, and therefore include racemates and stereoisomers, such as diastereomers and enantiomers, in both pure form and in admixture. Such stereoisomers can be prepared using conventional techniques, either by reacting enantiomeric starting materials, or by separating isomers of compounds of the present invention.

Isomers may include geometric isomers, for example cis isomers or trans isomers across a double bond. All such isomers are contemplated among the compounds of the present invention.

The compounds of the present invention also include tautomers.

The compounds of the present invention as discussed below include their salts, solvates and prodrugs.

Compound Syntheses

The starting materials for use in the preparation of the compounds of the invention are known or can be prepared by conventional methods known to a skilled person or in an analogous manner to processes described in the art.

Generally, the compounds of the present invention can be prepared by the procedures described below.

For example, as shown in Scheme I, reaction of aldehyde II with formaldehyde and sodium hydroxide yields the hydroxyaldehyde III which is converted to mesylate IV with methansulfonyl chloride and triethylamine similar to the procedure described in Chem. Ber. 98, 728-734 (1965). Reaction of mesylate IV with thiophenol V, prepared by the procedure described in WO 93/16055, in the presence of triethylamine yields keto-aldehyde VI which can be cyclized with the reagent, prepared from zinc and titanium trichloride in refluxing ethylene glycol dimethyl ether (DME), to give a mixture of 2,3-dihydrobenzothiepine VII and two racemic steroisomers of benzothiepin-(5H)-4-one VIII when R¹ and R² are nonequivalent. Oxidation of VII with 3 equivalents of m-chloro-perbenzoic acid (MCPBA) gives isomeric sulfone-epoxides IX which upon hydrogenation with palladium on carbon as the catalyst yield a mixture of four racemic stereoisomers of 4-hydroxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxides X and two racemic stereoisomers of 2,3,4,5-tetrahydrobenzothiepine-1,1-dioxides XI when R¹ and R² are nonequivalent.

Optically active compounds of the present invention can be prepared by using optically active starting material III or by resolution of compounds X with optical resolution agents well known in the art as described in J. Org. Chem., 39, 3904 (1974), ibid., 42, 2781 (1977), and ibid., 44, 4891 (1979).

Alternatively, keto-aldehyde VI where R² is H can be prepared by reaction of thiophenol V with a 2-substituted acrolein.

Benzothiepin-(5H)-4-one VIII can be oxidized with MCPBA to give the benzothiepin-(5H)-4-one-1,1-dioxide XII which can be reduced with sodium borohydride to give four racemic stereoisomers of X. The two stereoisomers of X, Xa and Xb, having the OH group and R⁵ on the opposite sides of the benzothiepine ring can be converted to the other two isomers of X, Xc and Xd, having the OH group and R⁵ on the same side of the benzothiepine ring by reaction in methylene chloride with 40-50% sodium hydroxide in the presence of a phase transfer catalyst (PTC). The transformation can also be carried out with potassium t-butoxide in THF.

The compounds of the present invention where R⁵ is OR, NRR′ and S(O)_(n)R and R⁴ is hydroxy can be prepared by reaction of epoxide IX where R⁵ is H with thiol, alcohol, and amine in the presence of a base.

Another route to Xc and Xd of the present invention is shown in Scheme 2. Compound VI is oxidized to compound XIII with two equivalent of m-chloroperbenzoic acid. Hydrogenolysis of compound XIII with palladium on carbon yields compound XIV which can be cyclized with either potassium t-butoxide or sodium hydroxide under phase transfer conditions to a mixture of Xc and Xd. Separation of Xc and Xd can be accomplished by either HPLC or fractional crystallization.

The thiophenols XVIII and V used in the present invention can also be prepared according to the Scheme 3. Alkylation of phenol XV with an arylmethyl chloride in a nonpolar solvent according to the procedure in J. Chem. Soc., 2431-2432 (1958) gives the ortho substituted phenol XVI. The phenol XVI can be converted to the thiophenol XVIII via the thiocarbamate XVII by the procedure described in J. Org. Chem., 31, 3980 (1966). The phenol XVI is first reacted with dimethyl thiocarbamoyl chloride and triethylamine to give thiocarbamate XVII which is thermally rearranged at 200-300° C., and the rearranged product is hydrolyzed with sodium hydroxide to yield the thiophenol XVIII. Similarly, Thiophenol V can also be prepared from 2-acylphenol XIX via the intermediate thiocarbamate XX.

Scheme 4 shows another route to benzothiepine-1,1-dioxides Xc and Xd starting from the thiophenol XVIII. Compound XVIII can be reacted with mesylate IV to give the sulfide-aldehyde XXI. Oxidation of XXI with two equivalents of MCPBA yields the sulfone-aldehyde XIV which can be cyclized with potassium t-butoxide to a mixture of Xc and Xd. Cyclyzation of sulfide-aldehyde with potassium t-butoxide also gives a mixture of benzothiepine XXIIc and XXIId.

Examples of amine- and hydroxylamine-containing compounds of the present invention can be prepared as shown in Scheme 5 and Scheme 6. 2-Chloro-4-nitrobenzophenone is reduced with triethylsilane and trifluoromethane sulfonic acid to 2-chloro-4-nitrodiphenylmethane 32. Reaction of 32 with lithium sulfide followed by reacting the resulting sulfide with mesylate IV gives sulfide-aldehyde XXIII. Oxidation of XXIII with 2 equivalents of MCPBA yields sulfone-aldehyde XXIV which can be reduced by hydrogenation to the hydroxylamine XXV. Protecting the hydroxylamine XXV with di-t-butyldicarbonate gives the N,O-di-(t-butoxycarbonyl)hydroxylamino derivative XXVI. Cyclization of XXVI with potassium t-butoxide and removal of the t-butoxycarbonyl protecting group gives a mixture of hydroxylamino derivatives XXVIIc and XXVIId. The primary amine XXXIIIc and XXXIIId derivatives can also be prepared by further hydrogenation of XXIV or XXVIIc and XXVIId.

In Scheme 6, reduction of the sulfone-aldehyde XXV with hydrogen followed by reductive alkylation of the resulting amino derivative with hydrogen and an aldehyde catalyzed by palladium on carbon in the same reaction vessel yields the substituted amine derivative XXVIII. Cyclization of XXVIII with potassium t-butoxide yields a mixture of substituted amino derivatives of this invention XXIXc and XXIXd.

Scheme 7 describes one of the methods of introducing a substituent to the aryl ring at the 5-position of benzothiepine. Iodination of 5-phenyl derivative XXX with iodine catalyzed by mercuric triflate gives the iodo derivative XXXI, which upon palladium-catalyzed carbonylation in an alcohol yields the carboxylate XXXII. Hydrolysis of the carboxylate and derivatization of the resulting acid to acid derivatives are well known in the art.

Abbreviations used in the foregoing description have the following meanings:

THF—tetrahydrofuran

PTC—phase transfer catalyst

Aliquart 336—methyltricaprylylammonium chloride

MCPBA—m-chloroperbenzoic acid

Celite—a brand of diatomaceous earth filtering aid

DMF—dimethylformamide

DME—ethylene glycol dimethyl ether

BOC—t-butoxycarbonyl group

Me—methyl

Et—ethyl

Bu—butyl

EtOAc—ethyl acetate

Et₂O—diethyl ether

CH₂Cl₂—methylene chloride

MgSO₄—magnesium sulfate

NaOH—sodium hydroxide

CH₃OH—methanol

HCl—hydrochloric acid

NaCl—sodium chloride

NaH—sodium hydride

LAH—lithium aluminum hydride

LiOH—lithium hydroxide

Na₂SO₃—sodium sulfite

NaHCO₃—sodium bicarbonate

DMSO—dimethylsulfoxide

KOSiMe₃—potassium trimethylsilanolate

PEG—polyethylene glycol

MS—mass spectrometry

HRMS—high resolution mass spectrometry

ES —electrospray

NMR—nuclear magnetic resonance spectroscopy

GC—gas chromatography

MPLC—medium pressure liquid chromatography

HPLC—high pressure liquid chromatography

RPHPLC—reverse phase high pressure liquid chromatography

RT—room temperature

h or hr—hour(s)

min—minute(s)

“Enantiomerically-enriched” (e.e.) means that one enantiomer or set of diastereomers preponderates over the complementary enantiomer or set of diastereomers. Enantiomeric enrichment of a mixture of enantiomers is calculated by dividing the concentration of the preponderating enantiomer by the concentration of the other enantiomer, multiplying the dividend by 100, and expressing the result as a percent. Enantiomeric enrichment can be from about 1% to about 100%, preferably from about 10% to about 100%, and more preferably from about 20% to 100%.

R¹ and R² can be selected from among substituted and unsubstituted C₁ to C₁₀ alkyl wherein the substituent(s) can be selected from among alkylcarbonyl, alkoxy, hydroxy, and nitrogen-containing heterocycles joined to the C₁ to C₁₀ alkyl through an ether linkage. Substituents at the 3-carbon can include ethyl, n-propyl, n-butyl, n-pentyl, isobutyl, isopropyl, —CH₂C(═O)C₂H₅, —CH₂OC₂H₅, and —CH₂O—(4-picoline). Ethyl, n-propyl, n-butyl, and isobutyl are preferred. In certain particularly preferred compounds of the present invention, substituents R¹ and R² are identical, for example n-butyl/n-butyl, so that the compound is achiral at the 3-carbon. Eliminating optical isomerism at the 3-carbon simplifies the selection, synthesis, separation, and quality control of the compound used as an ileal bile acid transport inhibitor. In both compounds having a chiral 3-carbon and those having an achiral 3-carbon, substituents (R^(x)) on the benzo-ring can include hydrogen, aryl, alkyl, hydroxy, halo, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, haloalkyl, haloalkoxy, (N)-hydroxy-carbonylalkyl amine, haloalkylthio, haloalkylsulfinyl, haloalkylsufonyl, amino, N-alkylamino, N,N-dialkylamino, (N)-alkoxycarbamoyl, (N)-aryloxycarbamoyl, (N)-aralkyloxycarbamoyl, trialkylammonium (especially with a halide counterion), (N)-amido, (N)-alkylamido, —N-alkylamido, —N,N-dialkylamido, (N)-haloalkylamido, (N)-sulfonamido, (N)-alkylsulfonamido, (N)-haloalkylsulfonamido, carboxyalkyl-amino, trialkylammonium salt, (N)-carbamic acid, alkyl or benzyl ester, N-acylamine, hydroxylamine, haloacylamine, carbohydrate, thiophene a trialkyl ammonium salt having a carboxylic acid or hydroxy substituent on one or more of the alkyl substituents, an alkylene bridge having a quaternary ammonium salt substituted thereon, —[O(CH₂)_(w)]_(x)—X where x is 2 to 12, w is 2 or 3 and X is a halo or a quaternary ammonium salt, and (N)-nitrogen containing heterocycle wherein the nitrogen of said heterocycle is optionally quaternized. Among the preferred species which may constitute R^(x) are methyl, ethyl, isopropyl, t-butyl, hydroxy, methoxy, ethoxy, isopropoxy, methylthio, iodo, bromo, fluoro, methylsulfinyl, methylsulfonyl, ethylthio, amino, hydroxylamine, N-methylamino, N,N-dimethylamino, N,N-diethylamino, (N)-benzyloxycarbamoyl, trimethylammonium, A⁻, —NHC(═O)CH₃, —NHC(═O)C₅H₁₁, —NHC(═O)C₆H₁₃, carboxyethylamino, (N)-morpholinyl, (N)-azetidinyl, (N)-N-methylazetidinium A⁻, (N)-pyrrolidinyl, pyrrolyl, (N)-N-methylpyridinium A⁻, (N)-N-methylmorpholinium A⁻, and N-N′-methylpiperazinyl, (N)-bromomethylamido, (N)-N-hexylamino, thiophene, —N⁺(CH₃)₂CO₂HI⁻, —NCH₃CH₂CO₂H, —(N)-N′-dimethylpiperazinium I⁻, (N)-t-butyloxycarbamoyl, (N)-methylsulfonamido, (N)N′-methylpyrrolidinium, and —(OCH₂CH₂)₃I, where A⁻ is a pharmaceutically acceptable anion. The benzo ring is can be mono-substituted at the 6, 7 or 8 position, or disubstituted at the 7- and -8 positions. Also included are the 6,7,8-trialkoxy compounds, for example the 6,7,8-trimethoxy compounds. A variety of other substituents can be advantageously present on the 6, 7, 8, and/or 9-positions of the benzo ring, including, for example, guanidinyl, cycloalkyl, carbohydrate (e.g., a 5 or 6 carbon monosaccharide), peptide, and quaternary ammonium salts linked to the ring via poly(oxyalkylene) linkages, e.g., —(OCH₂CH₂)_(x)—N⁺R¹³R¹⁴R¹⁵A⁻, where x is 2 to 10. Exemplary compounds are those set forth below in Table 1.

TABLE 1 Alternative Compounds #3 (Family F101.xxx.yyy)

Prefix Cpd # (FFF.xxx. yyy) R¹ = R² R⁵ (R^(x))q F101.001 01 ethyl Ph— 7-methyl 02 ethyl Ph— 7-ethyl 03 ethyl Ph— 7-iso-propyl 04 ethyl Ph— 7-tert-butyl 05 ethyl Ph— 7-OH 06 ethyl Ph— 7-OCH₃ 07 ethyl Ph— 7-O(iso-propyl) 08 ethyl Ph— 7-SCH₃ 09 ethyl Ph— 7-SOCH₃ 10 ethyl Ph— 7-SO₂CH₃ 11 ethyl Ph— 7-SCH₂CH₃ 12 ethyl Ph— 7-NH₂ 13 ethyl Ph— 7-NHOH 14 ethyl Ph— 7-NHCH₃ 15 ethyl Ph— 7-N(CH₃)₂ 16 ethyl Ph— 7-N⁺(CH₃)₃, I⁻ 17 ethyl Ph— 7-NHC(═O)CH₃ 18 ethyl Ph— 7-N(CH₂CH₃)₂ 19 ethyl Ph— 7-NMeCH₂CO₂H 20 ethyl Ph— 7-N⁺(Me)₂CH₂CO₂H, I⁻ 21 ethyl Ph— 7-(N)-morpholine 22 ethyl Ph— 7-(N)-azetidine 23 ethyl Ph— 7-(N)-N-methylazetidinium, I⁻ 24 ethyl Ph— 7-(N)-pyrrolidine 25 ethyl Ph— 7-(N)-N-methyl-pyrrolidinium, I⁻ 26 ethyl Ph— 7-(N)-N-methyl-morpholinium, I⁻ 27 ethyl Ph— 7-(N)-N′-methylpiperazine 28 ethyl Ph— 7-(N)-N′-dimethylpiperazinium, I⁻ 29 ethyl Ph— 7-NH—CBZ 30 ethyl Ph— 7-NHC(O)C₅H₁₁ 31 ethyl Ph— 7-NHC(O)CH₂Br 32 ethyl Ph— 7-NH—C(NH)NH₂ 33 ethyl Ph— 7-(2)-thiophene 34 ethyl Ph— 8-methyl 35 ethyl Ph— 8-ethyl 36 ethyl Ph— 8-iso-propyl 37 ethyl Ph— 8-tert-butyl 38 ethyl Ph— 8-OH 39 ethyl Ph— 8-OCH₃ 40 ethyl Ph— 8-O(iso-propyl) 41 ethyl Ph— 8-SCH₃ 42 ethyl Ph— 8-SOCH₃ 43 ethyl Ph— 8-SO₂CH₃ 44 ethyl Ph— 8-SCH₂CH₃ 45 ethyl Ph— 8-NH₂ 46 ethyl Ph— 8-NHOH 47 ethyl Ph— 8-NHCH₃ 48 ethyl Ph— 8-N(CH₃)₂ 49 ethyl Ph— 8-N⁺(CH₃)₃, I⁻ 50 ethyl Ph— 8-NHC(═O)CH₃ 51 ethyl Ph— 8-N(CH₂CH₃)₂ 52 ethyl Ph— 8-NMeCH₂CO₂H 53 ethyl Ph— 8-N⁺(Me)₂CH₂CO₂H, I⁻ 54 ethyl Ph— 8-(N)-morpholine 55 ethyl Ph— 8-(N)-azetidine 56 ethyl Ph— 8-(N)-N-methylazetidinium, I⁻ 57 ethyl Ph— 8-(N)-pyrrolidine 58 ethyl Ph— 8-(N)-N-methyl-pyrrolidinium, I ⁻ 59 ethyl Ph— 8-(N)-N-methyl-morpholinium, I⁻ 60 ethyl Ph— 8-(N)-N′-methylpiperazine 61 ethyl Ph— 8-(N)-N′-dimethylpiperazinium, I⁻ 62 ethyl Ph— 8-NH—CBZ 63 ethyl Ph— 8-NHC(O)C₅H₁₁ 64 ethyl Ph— 8-NHC(O)CH₂Br 65 ethyl Ph— 8-NH—C(NH)NH₂ 66 ethyl Ph— 8-(2)-thiophene 67 ethyl Ph— 9-methyl 68 ethyl Ph— 9-ethyl 69 ethyl Ph— 9-iso-propyl 70 ethyl Ph— 9-tert-butyl 71 ethyl Ph— 9-OH 72 ethyl Ph— 9-OCH₃ 73 ethyl Ph— 9-O(iso-propyl) 74 ethyl Ph— 9-SCH₃ 75 ethyl Ph— 9-SOCH₃ 76 ethyl Ph— 9-SO₂CH₃ 77 ethyl Ph— 9-SCH₂CH₃ 78 ethyl Ph— 9-NH₂ 79 ethyl Ph— 9-NHOH 80 ethyl Ph— 9-NHCH₃ 81 ethyl Ph— 9-N(CH₃)₂ 82 ethyl Ph— 9-N⁺(CH₃)₃, I⁻ 83 ethyl Ph— 9-NHC(═O)CH₃ 84 ethyl Ph— 9-N(CH₂CH₃)₂ 85 ethyl Ph— 9-NMeCH₂CO₂H 86 ethyl Ph— 9-N⁺(Me)₂CH₂CO₂H, I⁻ 87 ethyl Ph— 9-(N)-morpholine 88 ethyl Ph— 9-(N)-azetidine 89 ethyl Ph— 9-(N)-N-methylazetidinium, I⁻ 90 ethyl Ph— 9-(N)-pyrrolidine 91 ethyl Ph— 9-(N)-N-methyl-pyrrolidinium, I⁻ 92 ethyl Ph— 9-(N)-N-methyl-morpholinium, I⁻ 93 ethyl Ph— 9-(N)-N′-methylpiperazine 93 ethyl Ph— 9-(N)-N′-dimethylpiperazinium, I⁻ 95 ethyl Ph— 9-NH—CBZ 96 ethyl Ph— 9-NHC(O)C₅H₁₁ 97 ethyl Ph— 9-NHC(O)CH₂Br 98 ethyl Ph— 9-NH—C(NH)NH₂ 99 ethyl Ph— 9-(2)-thiophene 100 ethyl Ph— 7-OCH₃, 8-OCH₃ 101 ethyl Ph— 7-SCH₃, 8-OCH₃ 102 ethyl Ph— 7-SCH₃, 8-SCH₃ 103 ethyl Ph— 6-OCH₃, 7-OCH₃, 8-OCH₃ F101.002 01 n-propyl Ph— 7-methyl 02 n-propyl Ph— 7-ethyl 03 n-propyl Ph— 7-iso-propyl 04 n-propyl Ph— 7-tert-butyl 05 n-propyl Ph— 7-OH 06 n-propyl Ph— 7-OCH₃ 07 n-propyl Ph— 7-O(iso-propyl) 08 n-propyl Ph— 7-SCH₃ 09 n-propyl Ph— 7-SOCH₃ 10 n-propyl Ph— 7-SO₂CH₃ 11 n-propyl Ph— 7-SCH₂CH₃ 12 n-propyl Ph— 7-NH₂ 13 n-propyl Ph— 7-NHOH 14 n-propyl Ph— 7-NHCH₃ 15 n-propyl Ph— 7-N(CH₃)₂ 16 n-propyl Ph— 7-N⁺(CH₃)₃, I⁻ 17 n-propyl Ph— 7-NHC(═O)CH₃ 18 n-propyl Ph— 7-N(CH₂CH₃)₂ 19 n-propyl Ph— 7-NMeCH₂CO₂H 20 n-propyl Ph— 7-N⁺(Me)₂CH₂CO₂H, I⁻ 21 n-propyl Ph— 7-(N)-morpholine 22 n-propyl Ph— 7-(N)-azetidine 23 n-propyl Ph— 7-(N)-N-methylazetidinium, I⁻ 24 n-propyl Ph— 7-(N)-pyrrolidine 25 n-propyl Ph— 7-(N)-N-methyl-pyrrolidinium, I⁻ 26 n-propyl Ph— 7-(N)-N-methyl-morpholinium, I⁻ 27 n-propyl Ph— 7-(N)-N′-methylpiperazine 28 n-propyl Ph— 7-(N)-N′-dimethylpiperazinium, I⁻ 29 n-propyl Ph— 7-NH—CBZ 30 n-propyl Ph— 7-NHC(O)C₅H₁₁ 31 n-propyl Ph— 7-NHC(O)CH₂Br 32 n-propyl Ph— 7-NH—C(NH)NH₂ 33 n-propyl Ph— 7-(2)-thiophene 34 n-propyl Ph— 8-methyl 35 n-propyl Ph— 8-ethyl 36 n-propyl Ph— 8-iso-propyl 37 n-propyl Ph— 8-tert-butyl 38 n-propyl Ph— 8-OH 39 n-propyl Ph— 8-OCH₃ 40 n-propyl Ph— 8-O(iso-propyl) 41 n-propyl Ph— 8-SCH₃ 42 n-propyl Ph— 8-SOCH₃ 43 n-propyl Ph— 8-SO₂CH₃ 44 n-propyl Ph— 8-SCH₂CH₃ 45 n-propyl Ph— 8-NH₂ 46 n-propyl Ph— 8-NHOH 47 n-propyl Ph— 8-NHCH₃ 48 n-propyl Ph— 8-N(CH₃)₂ 49 n-propyl Ph— 8-N⁺(CH₃)₃, I⁻ 50 n-propyl Ph— 8-NHC(═O)CH₃ 51 n-propyl Ph— 8-N(CH₂CH₃)₂ 52 n-propyl Ph— 8-NMeCH₂CO₂H 53 n-propyl Ph— 8-N⁺(Me)₂CH₂CO₂H, I⁻ 54 n-propyl Ph— 8-(N)-morpholine 55 n-propyl Ph— 8-(N)-azetidine 56 n-propyl Ph— 8-(N)-N-methylazetidinium, I⁻ 57 n-propyl Ph— 8-(N)-pyrrolidine 58 n-propyl Ph— 8-(N)-N-methyl-pyrrolidinium, I ⁻ 59 n-propyl Ph— 8-(N)-N-methyl-morpholinium, I⁻ 60 n-propyl Ph— 8-(N)-N′-methylpiperazine 61 n-propyl Ph— 8-(N)-N′-dimethylpiperazinium, I⁻ 62 n-propyl Ph— 8-NH—CBZ 63 n-propyl Ph— 8-NHC(O)C₅H₁₁ 64 n-propyl Ph— 8-NHC(O)CH₂Br 65 n-propyl Ph— 8-NH—C(NH)NH₂ 66 n-propyl Ph— 8-(2)-thiophene 67 n-propyl Ph— 9-methyl 68 n-propyl Ph— 9-ethyl 69 n-propyl Ph— 9-iso-propyl 70 n-propyl Ph— 9-tert-butyl 71 n-propyl Ph— 9-OH 72 n-propyl Ph— 9-OCH₃ 73 n-propyl Ph— 9-O(iso-propyl) 74 n-propyl Ph— 9-SCH₃ 75 n-propyl Ph— 9-SOCH₃ 76 n-propyl Ph— 9-SO₂CH₃ 77 n-propyl Ph— 9-SCH₂CH₃ 78 n-propyl Ph— 9-NH₂ 79 n-propyl Ph— 9-NHOH 80 n-propyl Ph— 9-NHCH₃ 81 n-propyl Ph— 9-N(CH₃)₂ 82 n-propyl Ph— 9-N⁺(CH₃)₃, I⁻ 83 n-propyl Ph— 9-NHC(═O)CH₃ 84 n-propyl Ph— 9-N(CH₂CH₃)₂ 85 n-propyl Ph— 9-NMeCH₂CO₂H 86 n-propyl Ph— 9-N⁺(Me)₂CH₂CO₂H, I⁻ 87 n-propyl Ph— 9-(N)-morpholine 88 n-propyl Ph— 9-(N)-azetidine 89 n-propyl Ph— 9-(N)-N-methylazetidinium, I⁻ 90 n-propyl Ph— 9-(N)-pyrrolidine 91 n-propyl Ph— 9-(N)-N-methyl-pyrrolidinium, I⁻ 92 n-propyl Ph— 9-(N)-N-methyl-morpholinium, I⁻ 93 n-propyl Ph— 9-(N)-N′-methylpiperazine 93 n-propyl Ph— 9-(N)-N′-dimethylpiperazinium, I⁻ 95 n-propyl Ph— 9-NH—CBZ 96 n-propyl Ph— 9-NHC(O)C₅H₁₁ 97 n-propyl Ph— 9-NHC(O)CH₂Br 98 n-propyl Ph— 9-NH—C(NH)NH₂ 99 n-propyl Ph— 9-(2)-thiophene 100 n-propyl Ph— 7-OCH₃, 8-OCH₃ 101 n-propyl Ph— 7-SCH₃, 8-OCH₃ 102 n-propyl Ph— 7-SCH₃, 8-SCH₃ 103 n-propyl Ph— 6-OCH₃, 7-OCH₃, 8-OCH₃ F101.003 01 n-butyl Ph— 7-methyl 02 n-butyl Ph— 7-ethyl 03 n-butyl Ph— 7-iso-propyl 04 n-butyl Ph— 7-tert-butyl 05 n-butyl Ph— 7-OH 06 n-butyl Ph— 7-OCH₃ 07 n-butyl Ph— 7-O(iso-propyl) 08 n-butyl Ph— 7-SCH₃ 09 n-butyl Ph— 7-SOCH₃ 10 n-butyl Ph— 7-SO₂CH₃ 11 n-butyl Ph— 7-SCH₂CH₃ 12 n-butyl Ph— 7-NH₂ 13 n-butyl Ph— 7-NHOH 14 n-butyl Ph— 7-NHCH₃ 15 n-butyl Ph— 7-N(CH₃)₂ 16 n-butyl Ph— 7-N⁺(CH₃)₃, I⁻ 17 n-butyl Ph— 7-NHC(═O)CH₃ 18 n-butyl Ph— 7-N(CH₂CH₃)₂ 19 n-butyl Ph— 7-NMeCH₂CO₂H 20 n-butyl Ph— 7-N⁺(Me)₂CH₂CO₂H, I⁻ 21 n-butyl Ph— 7-(N)-morpholine 22 n-butyl Ph— 7-(N)-azetidine 23 n-butyl Ph— 7-(N)-N-methylazetidinium, I⁻ 24 n-butyl Ph— 7-(N)-pyrrolidine 25 n-butyl Ph— 7-(N)-N-methyl-pyrrolidinium, I⁻ 26 n-butyl Ph— 7-(N)-N-methyl-morpholinium, I⁻ 27 n-butyl Ph— 7-(N)-N′-methylpiperazine 28 n-butyl Ph— 7-(N)-N′-dimethylpiperazinium, I⁻ 29 n-butyl Ph— 7-NH—CBZ 30 n-butyl Ph— 7-NHC(O)C₅H₁₁ 31 n-butyl Ph— 7-NHC(O)CH₂Br 32 n-butyl Ph— 7-NH—C(NH)NH₂ 33 n-butyl Ph— 7-(2)-thiophene 34 n-butyl Ph— 8-methyl 35 n-butyl Ph— 8-ethyl 36 n-butyl Ph— 8-iso-propyl 37 n-butyl Ph— 8-tert-butyl 38 n-butyl Ph— 8-OH 39 n-butyl Ph— 8-OCH₃ 40 n-butyl Ph— 8-O(iso-propyl) 41 n-butyl Ph— 8-SCH₃ 42 n-butyl Ph— 8-SOCH₃ 43 n-butyl Ph— 8-SO₂CH₃ 44 n-butyl Ph— 8-SCH₂CH₃ 45 n-butyl Ph— 8-NH₂ 46 n-butyl Ph— 8-NHOH 47 n-butyl Ph— 8-NHCH₃ 48 n-butyl Ph— 8-N(CH₃)₂ 49 n-butyl Ph— 8-N⁺(CH₃)₃, I⁻ 50 n-butyl Ph— 8-NHC(═O)CH₃ 51 n-butyl Ph— 8-N(CH₂CH₃)₂ 52 n-butyl Ph— 8-NMeCH₂CO₂H 53 n-butyl Ph— 8-N⁺(Me)₂CH₂CO₂H, I⁻ 54 n-butyl Ph— 8-(N)-morpholine 55 n-butyl Ph— 8-(N)-azetidine 56 n-butyl Ph— 8-(N)-N-methylazetidinium, I⁻ 57 n-butyl Ph— 8-(N)-pyrrolidine 58 n-butyl Ph— 8-(N)-N-methyl-pyrrolidinium, I ⁻ 59 n-butyl Ph— 8-(N)-N-methyl-morpholinium, I⁻ 60 n-butyl Ph— 8-(N)-N′-methylpiperazine 61 n-butyl Ph— 8-(N)-N′-dimethylpiperazinium, I⁻ 62 n-butyl Ph— 8-NH—CBZ 63 n-butyl Ph— 8-NHC(O)C₅H₁₁ 64 n-butyl Ph— 8-NHC(O)CH₂Br 65 n-butyl Ph— 8-NH—C(NH)NH₂ 66 n-butyl Ph— 8-(2)-thiophene 67 n-butyl Ph— 9-methyl 68 n-butyl Ph— 9-ethyl 69 n-butyl Ph— 9-iso-propyl 70 n-butyl Ph— 9-tert-butyl 71 n-butyl Ph— 9-OH 72 n-butyl Ph— 9-OCH₃ 73 n-butyl Ph— 9-O(iso-propyl) 74 n-butyl Ph— 9-SCH₃ 75 n-butyl Ph— 9-SOCH₃ 76 n-butyl Ph— 9-SO₂CH₃ 77 n-butyl Ph— 9-SCH₂CH₃ 78 n-butyl Ph— 9-NH₂ 79 n-butyl Ph— 9-NHOH 80 n-butyl Ph— 9-NHCH₃ 81 n-butyl Ph— 9-N(CH₃)₂ 82 n-butyl Ph— 9-N⁺(CH₃)₃, I⁻ 83 n-butyl Ph— 9-NHC(═O)CH₃ 84 n-butyl Ph— 9-N(CH₂CH₃)₂ 85 n-butyl Ph— 9-NMeCH₂CO₂H 86 n-butyl Ph— 9-N⁺(Me)₂CH₂CO₂H, I⁻ 87 n-butyl Ph— 9-(N)-morpholine 88 n-butyl Ph— 9-(N)-azetidine 89 n-butyl Ph— 9-(N)-N-methylazetidinium, I⁻ 90 n-butyl Ph— 9-(N)-pyrrolidine 91 n-butyl Ph— 9-(N)-N-methyl-pyrrolidinium, I⁻ 92 n-butyl Ph— 9-(N)-N-methyl-morpholinium, I⁻ 93 n-butyl Ph— 9-(N)-N′-methylpiperazine 93 n-butyl Ph— 9-(N)-N′-dimethylpiperazinium, I⁻ 95 n-butyl Ph— 9-NH—CBZ 96 n-butyl Ph— 9-NHC(O)C₅H₁₁ 97 n-butyl Ph— 9-NHC(O)CH₂Br 98 n-butyl Ph— 9-NH—C(NH)NH₂ 99 n-butyl Ph— 9-(2)-thiophene 100 n-butyl Ph— 7-OCH₃, 8-OCH₃ 101 n-butyl Ph— 7-SCH₃, 8-OCH₃ 102 n-butyl Ph— 7-SCH₃, 8-SCH₃ 103 n-butyl Ph— 6-OCH₃, 7-OCH₃, 8-OCH₃ F101.004 01 n-pentyl Ph— 7-methyl 02 n-pentyl Ph— 7-ethyl 03 n-pentyl Ph— 7-iso-propyl 04 n-pentyl Ph— 7-tert-butyl 05 n-pentyl Ph— 7-OH 06 n-pentyl Ph— 7-OCH₃ 07 n-pentyl Ph— 7-O(iso-propyl) 08 n-pentyl Ph— 7-SCH₃ 09 n-pentyl Ph— 7-SOCH₃ 10 n-pentyl Ph— 7-SO₂CH₃ 11 n-pentyl Ph— 7-SCH₂CH₃ 12 n-pentyl Ph— 7-NH₂ 13 n-pentyl Ph— 7-NHOH 14 n-pentyl Ph— 7-NHCH₃ 15 n-pentyl Ph— 7-N(CH₃)₂ 16 n-pentyl Ph— 7-N⁺(CH₃)₃, I⁻ 17 n-pentyl Ph— 7-NHC(═O)CH₃ 18 n-pentyl Ph— 7-N(CH₂CH₃)₂ 19 n-pentyl Ph— 7-NMeCH₂CO₂H 20 n-pentyl Ph— 7-N⁺(Me)₂CH₂CO₂H, I⁻ 21 n-pentyl Ph— 7-(N)-morpholine 22 n-pentyl Ph— 7-(N)-azetidine 23 n-pentyl Ph— 7-(N)-N-methylazetidinium, I⁻ 24 n-pentyl Ph— 7-(N)-pyrrolidine 25 n-pentyl Ph— 7-(N)-N-methyl-pyrrolidinium, I⁻ 26 n-pentyl Ph— 7-(N)-N-methyl-morpholinium, I⁻ 27 n-pentyl Ph— 7-(N)-N′-methylpiperazine 28 n-pentyl Ph— 7-(N)-N′-dimethylpiperazinium, I⁻ 29 n-pentyl Ph— 7-NH—CBZ 30 n-pentyl Ph— 7-NHC(O)C₅H₁₁ 31 n-pentyl Ph— 7-NHC(O)CH₂Br 32 n-pentyl Ph— 7-NH—C(NH)NH₂ 33 n-pentyl Ph— 7-(2)-thiophene 34 n-pentyl Ph— 8-methyl 35 n-pentyl Ph— 8-ethyl 36 n-pentyl Ph— 8-iso-propyl 37 n-pentyl Ph— 8-tert-butyl 38 n-pentyl Ph— 8-OH 39 n-pentyl Ph— 8-OCH₃ 40 n-pentyl Ph— 8-O(iso-propyl) 41 n-pentyl Ph— 8-SCH₃ 42 n-pentyl Ph— 8-SOCH₃ 43 n-pentyl Ph— 8-SO₂CH₃ 44 n-pentyl Ph— 8-SCH₂CH₃ 45 n-pentyl Ph— 8-NH₂ 46 n-pentyl Ph— 8-NHOH 47 n-pentyl Ph— 8-NHCH₃ 48 n-pentyl Ph— 8-N(CH₃)₂ 49 n-pentyl Ph— 8-N⁺(CH₃)₃, I⁻ 50 n-pentyl Ph— 8-NHC(═O)CH₃ 51 n-pentyl Ph— 8-N(CH₂CH₃)₂ 52 n-pentyl Ph— 8-NMeCH₂CO₂H 53 n-pentyl Ph— 8-N⁺(Me)₂CH₂CO₂H, I⁻ 54 n-pentyl Ph— 8-(N)-morpholine 55 n-pentyl Ph— 8-(N)-azetidine 56 n-pentyl Ph— 8-(N)-N-methylazetidinium, I⁻ 57 n-pentyl Ph— 8-(N)-pyrrolidine 58 n-pentyl Ph— 8-(N)-N-methyl-pyrrolidinium, I ⁻ 59 n-pentyl Ph— 8-(N)-N-methyl-morpholinium, I⁻ 60 n-pentyl Ph— 8-(N)-N′-methylpiperazine 61 n-pentyl Ph— 8-(N)-N′-dimethylpiperazinium, I⁻ 62 n-pentyl Ph— 8-NH—CBZ 63 n-pentyl Ph— 8-NHC(O)C₅H₁₁ 64 n-pentyl Ph— 8-NHC(O)CH₂Br 65 n-pentyl Ph— 8-NH—C(NH)NH₂ 66 n-pentyl Ph— 8-(2)-thiophene 67 n-pentyl Ph— 9-methyl 68 n-pentyl Ph— 9-ethyl 69 n-pentyl Ph— 9-iso-propyl 70 n-pentyl Ph— 9-tert-butyl 71 n-pentyl Ph— 9-OH 72 n-pentyl Ph— 9-OCH₃ 73 n-pentyl Ph— 9-O(iso-propyl) 74 n-pentyl Ph— 9-SCH₃ 75 n-pentyl Ph— 9-SOCH₃ 76 n-pentyl Ph— 9-SO₂CH₃ 77 n-pentyl Ph— 9-SCH₂CH₃ 78 n-pentyl Ph— 9-NH₂ 79 n-pentyl Ph— 9-NHOH 80 n-pentyl Ph— 9-NHCH₃ 81 n-pentyl Ph— 9-N(CH₃)₂ 82 n-pentyl Ph— 9-N⁺(CH₃)₃, I⁻ 83 n-pentyl Ph— 9-NHC(═O)CH₃ 84 n-pentyl Ph— 9-N(CH₂CH₃)₂ 85 n-pentyl Ph— 9-NMeCH₂CO₂H 86 n-pentyl Ph— 9-N⁺(Me)₂CH₂CO₂H, I⁻ 87 n-pentyl Ph— 9-(N)-morpholine 88 n-pentyl Ph— 9-(N)-azetidine 89 n-pentyl Ph— 9-(N)-N-methylazetidinium, I⁻ 90 n-pentyl Ph— 9-(N)-pyrrolidine 91 n-pentyl Ph— 9-(N)-N-methyl-pyrrolidinium, I⁻ 92 n-pentyl Ph— 9-(N)-N-methyl-morpholinium, I⁻ 93 n-pentyl Ph— 9-(N)-N′-methylpiperazine 93 n-pentyl Ph— 9-(N)-N′-dimethylpiperazinium, I⁻ 95 n-pentyl Ph— 9-NH—CBZ 96 n-pentyl Ph— 9-NHC(O)C₅H₁₁ 97 n-pentyl Ph— 9-NHC(O)CH₂Br 98 n-pentyl Ph— 9-NH—C(NH)NH₂ 99 n-pentyl Ph— 9-(2)-thiophene 100 n-pentyl Ph— 7-OCH₃, 8-OCH₃ 101 n-pentyl Ph— 7-SCH₃, 8-OCH₃ 102 n-pentyl Ph— 7-SCH₃, 8-SCH₃ 103 n-pentyl Ph— 6-OCH₃, 7-OCH₃, 8-OCH₃ F101.005 01 n-hexyl Ph— 7-methyl 02 n-hexyl Ph— 7-ethyl 03 n-hexyl Ph— 7-iso-propyl 04 n-hexyl Ph— 7-tert-butyl 05 n-hexyl Ph— 7-OH 06 n-hexyl Ph— 7-OCH₃ 07 n-hexyl Ph— 7-O(iso-propyl) 08 n-hexyl Ph— 7-SCH₃ 09 n-hexyl Ph— 7-SOCH₃ 10 n-hexyl Ph— 7-SO₂CH₃ 11 n-hexyl Ph— 7-SCH₂CH₃ 12 n-hexyl Ph— 7-NH₂ 13 n-hexyl Ph— 7-NHOH 14 n-hexyl Ph— 7-NHCH₃ 15 n-hexyl Ph— 7-N(CH₃)₂ 16 n-hexyl Ph— 7-N⁺(CH₃)₃, I⁻ 17 n-hexyl Ph— 7-NHC(═O)CH₃ 18 n-hexyl Ph— 7-N(CH₂CH₃)₂ 19 n-hexyl Ph— 7-NMeCH₂CO₂H 20 n-hexyl Ph— 7-N⁺(Me)₂CH₂CO₂H, I⁻ 21 n-hexyl Ph— 7-(N)-morpholine 22 n-hexyl Ph— 7-(N)-azetidine 23 n-hexyl Ph— 7-(N)-N-methylazetidinium, I⁻ 24 n-hexyl Ph— 7-(N)-pyrrolidine 25 n-hexyl Ph— 7-(N)-N-methyl-pyrrolidinium, I⁻ 26 n-hexyl Ph— 7-(N)-N-methyl-morpholinium, I⁻ 27 n-hexyl Ph— 7-(N)-N′-methylpiperazine 28 n-hexyl Ph— 7-(N)-N′-dimethylpiperazinium, I ⁻ 29 n-hexyl Ph— 7-NH—CBZ 30 n-hexyl Ph— 7-NHC(O)C₅H₁₁ 31 n-hexyl Ph— 7-NHC(O)CH₂Br 32 n-hexyl Ph— 7-NH—C(NH)NH₂ 33 n-hexyl Ph— 7-(2)-thiophene 34 n-hexyl Ph— 8-methyl 35 n-hexyl Ph— 8-ethyl 36 n-hexyl Ph— 8-iso-propyl 37 n-hexyl Ph— 8-tert-butyl 38 n-hexyl Ph— 8-OH 39 n-hexyl Ph— 8-OCH₃ 40 n-hexyl Ph— 8-O(iso-propyl) 41 n-hexyl Ph— 8-SCH₃ 42 n-hexyl Ph— 8-SOCH₃ 43 n-hexyl Ph— 8-SO₂CH₃ 44 n-hexyl Ph— 8-SCH₂CH₃ 45 n-hexyl Ph— 8-NH₂ 46 n-hexyl Ph— 8-NHOH 47 n-hexyl Ph— 8-NHCH₃ 48 n-hexyl Ph— 8-N(CH₃)₂ 49 n-hexyl Ph— 8-N⁺(CH₃)₃, I⁻ 50 n-hexyl Ph— 8-NHC(═O)CH₃ 51 n-hexyl Ph— 8-N(CH₂CH₃)₂ 52 n-hexyl Ph— 8-NMeCH₂CO₂H 53 n-hexyl Ph— 8-N⁺(Me)₂CH₂CO₂H, I⁻ 54 n-hexyl Ph— 8-(N)-morpholine 55 n-hexyl Ph— 8-(N)-azetidine 56 n-hexyl Ph— 8-(N)-N-methylazetidinium, I⁻ 57 n-hexyl Ph— 8-(N)-pyrrolidine 58 n-hexyl Ph— 8-(N)-N-methyl-pyrrolidinium, I ⁻ 59 n-hexyl Ph— 8-(N)-N-methyl-morpholinium, I⁻ 60 n-hexyl Ph— 8-(N)-N′-methylpiperazine 61 n-hexyl Ph— 8-(N)-N′-dimethylpiperazinium, I⁻ 62 n-hexyl Ph— 8-NH—CBZ 63 n-hexyl Ph— 8-NHC(O)C₅H₁₁ 64 n-hexyl Ph— 8-NHC(O)CH₂Br 65 n-hexyl Ph— 8-NH—C(NH)NH₂ 66 n-hexyl Ph— 8-(2)-thiophene 67 n-hexyl Ph— 9-methyl 68 n-hexyl Ph— 9-ethyl 69 n-hexyl Ph— 9-iso-propyl 70 n-hexyl Ph— 9-tert-butyl 71 n-hexyl Ph— 9-OH 72 n-hexyl Ph— 9-OCH₃ 73 n-hexyl Ph— 9-O(iso-propyl) 74 n-hexyl Ph— 9-SCH₃ 75 n-hexyl Ph— 9-SOCH₃ 76 n-hexyl Ph— 9-SO₂CH₃ 77 n-hexyl Ph— 9-SCH₂CH₃ 78 n-hexyl Ph— 9-NH₂ 79 n-hexyl Ph— 9-NHOH 80 n-hexyl Ph— 9-NHCH₃ 81 n-hexyl Ph— 9-N(CH₃)₂ 82 n-hexyl Ph— 9-N⁺(CH₃)₃, I⁻ 83 n-hexyl Ph— 9-NHC(═O)CH₃ 84 n-hexyl Ph— 9-N(CH₂CH₃)₂ 85 n-hexyl Ph— 9-NMeCH₂CO₂H 86 n-hexyl Ph— 9-N⁺(Me)₂CH₂CO₂H, I⁻ 87 n-hexyl Ph— 9-(N)-morpholine 88 n-hexyl Ph— 9-(N)-azetidine 89 n-hexyl Ph— 9-(N)-N-methylazetidinium, I⁻ 90 n-hexyl Ph— 9-(N)-pyrrolidine 91 n-hexyl Ph— 9-(N)-N-methyl-pyrrolidinium, I⁻ 92 n-hexyl Ph— 9-(N)-N-methyl-morpholinium, I⁻ 93 n-hexyl Ph— 9-(N)-N′-methylpiperazine 93 n-hexyl Ph— 9-(N)-N′-dimethylpiperazinium, I⁻ 95 n-hexyl Ph— 9-NH—CBZ 96 n-hexyl Ph— 9-NHC(O)C₅H₁₁ 97 n-hexyl Ph— 9-NHC(O)CH₂Br 98 n-hexyl Ph— 9-NH—C(NH)NH₂ 99 n-hexyl Ph— 9-(2)-thiophene 100 n-hexyl Ph— 7-OCH₃, 8-OCH₃ 101 n-hexyl Ph— 7-SCH₃, 8-OCH₃ 102 n-hexyl Ph— 7-SCH₃, 8-SCH₃ 103 n-hexyl Ph— 6-OCH₃, 7-OCH₃, 8-OCH₃ F101.006 01 iso-propyl Ph— 7-methyl 02 iso-propyl Ph— 7-ethyl 03 iso-propyl Ph— 7-iso-propyl 04 iso-propyl Ph— 7-tert-butyl 05 iso-propyl Ph— 7-OH 06 iso-propyl Ph— 7-OCH₃ 07 iso-propyl Ph— 7-O(iso-propyl) 08 iso-propyl Ph— 7-SCH₃ 09 iso-propyl Ph— 7-SOCH₃ 10 iso-propyl Ph— 7-SO₂CH₃ 11 iso-propyl Ph— 7-SCH₂CH₃ 12 iso-propyl Ph— 7-NH₂ 13 iso-propyl Ph— 7-NHOH 14 iso-propyl Ph— 7-NHCH₃ 15 iso-propyl Ph— 7-N(CH₃)₂ 16 iso-propyl Ph— 7-N⁺(CH₃)₃, I⁻ 17 iso-propyl Ph— 7-NHC(═O)CH₃ 18 iso-propyl Ph— 7-N(CH₂CH₃)₂ 19 iso-propyl Ph— 7-NMeCH₂CO₂H 20 iso-propyl Ph— 7-N⁺(Me)₂CH₂CO₂H, I⁻ 21 iso-propyl Ph— 7-(N)-morpholine 22 iso-propyl Ph— 7-(N)-azetidine 23 iso-propyl Ph— 7-(N)-N-methylazetidinium, I⁻ 24 iso-propyl Ph— 7-(N)-pyrrolidine 25 iso-propyl Ph— 7-(N)-N-methyl-pyrrolidinium, I⁻ 26 iso-propyl Ph— 7-(N)-N-methyl-morpholinium, I⁻ 27 iso-propyl Ph— 7-(N)-N′-methylpiperazine 28 iso-propyl Ph— 7-(N)-N′-dimethylpiperazinium, I⁻ 29 iso-propyl Ph— 7-NH—CBZ 30 iso-propyl Ph— 7-NHC(O)C₅H₁₁ 31 iso-propyl Ph— 7-NHC(O)CH₂Br 32 iso-propyl Ph— 7-NH—C(NH)NH₂ 33 iso-propyl Ph— 7-(2)-thiophene 34 iso-propyl Ph— 8-methyl 35 iso-propyl Ph— 8-ethyl 36 iso-propyl Ph— 8-iso-propyl 37 iso-propyl Ph— 8-tert-butyl 38 iso-propyl Ph— 8-OH 39 iso-propyl Ph— 8-OCH₃ 40 iso-propyl Ph— 8-O(iso-propyl) 41 iso-propyl Ph— 8-SCH₃ 42 iso-propyl Ph— 8-SOCH₃ 43 iso-propyl Ph— 8-SO₂CH₃ 44 iso-propyl Ph— 8-SCH₂CH₃ 45 iso-propyl Ph— 8-NH₂ 46 iso-propyl Ph— 8-NHOH 47 iso-propyl Ph— 8-NHCH₃ 48 iso-propyl Ph— 8-N(CH₃)₂ 49 iso-propyl Ph— 8-N⁺(CH₃)₃, I⁻ 50 iso-propyl Ph— 8-NHC(═O)CH₃ 51 iso-propyl Ph— 8-N(CH₂CH₃)₂ 52 iso-propyl Ph— 8-NMeCH₂CO₂H 53 iso-propyl Ph— 8-N⁺(Me)₂CH₂CO₂H, I⁻ 54 iso-propyl Ph— 8-(N)-morpholine 55 iso-propyl Ph— 8-(N)-azetidine 56 iso-propyl Ph— 8-(N)-N-methylazetidinium, I⁻ 57 iso-propyl Ph— 8-(N)-pyrrolidine 58 iso-propyl Ph— 8-(N)-N-methyl-pyrrolidinium, I ⁻ 59 iso-propyl Ph— 8-(N)-N-methyl-morpholinium, I⁻ 60 iso-propyl Ph— 8-(N)-N′-methylpiperazine 61 iso-propyl Ph— 8-(N)-N′-dimethylpiperazinium, I⁻ 62 iso-propyl Ph— 8-NH—CBZ 63 iso-propyl Ph— 8-NHC(O)C₅H₁₁ 64 iso-propyl Ph— 8-NHC(O)CH₂Br 65 iso-propyl Ph— 8-NH—C(NH)NH₂ 66 iso-propyl Ph— 8-(2)-thiophene 67 iso-propyl Ph— 9-methyl 68 iso-propyl Ph— 9-ethyl 69 iso-propyl Ph— 9-iso-propyl 70 iso-propyl Ph— 9-tert-butyl 71 iso-propyl Ph— 9-OH 72 iso-propyl Ph— 9-OCH₃ 73 iso-propyl Ph— 9-O(iso-propyl) 74 iso-propyl Ph— 9-SCH₃ 75 iso-propyl Ph— 9-SOCH₃ 76 iso-propyl Ph— 9-SO₂CH₃ 77 iso-propyl Ph— 9-SCH₂CH₃ 78 iso-propyl Ph— 9-NH₂ 79 iso-propyl Ph— 9-NHOH 80 iso-propyl Ph— 9-NHCH₃ 81 iso-propyl Ph— 9-N(CH₃)₂ 82 iso-propyl Ph— 9-N⁺(CH₃)₃, I⁻ 83 iso-propyl Ph— 9-NHC(═O)CH₃ 84 iso-propyl Ph— 9-N(CH₂CH₃)₂ 85 iso-propyl Ph— 9-NMeCH₂CO₂H 86 iso-propyl Ph— 9-N⁺(Me)₂CH₂CO₂H, I⁻ 87 iso-propyl Ph— 9-(N)-morpholine 88 iso-propyl Ph— 9-(N)-azetidine 89 iso-propyl Ph— 9-(N)-N-methylazetidinium, I⁻ 90 iso-propyl Ph— 9-(N)-pyrrolidine 91 iso-propyl Ph— 9-(N)-N-methyl-pyrrolidinium, I⁻ 92 iso-propyl Ph— 9-(N)-N-methyl-morpholinium, I⁻ 93 iso-propyl Ph— 9-(N)-N′-methylpiperazine 93 iso-propyl Ph— 9-(N)-N′-dimethylpiperazinium, I⁻ 95 iso-propyl Ph— 9-NH—CBZ 96 iso-propyl Ph— 9-NHC(O)C₅H₁₁ 97 iso-propyl Ph— 9-NHC(O)CH₂Br 98 iso-propyl Ph— 9-NH—C(NH)NH₂ 99 iso-propyl Ph— 9-(2)-thiophene 100 iso-propyl Ph— 7-OCH₃, 8-OCH₃ 101 iso-propyl Ph— 7-SCH₃, 8-OCH₃ 102 iso-propyl Ph— 7-SCH₃, 8-SCH₃ 103 iso-propyl Ph— 6-OCH₃, 7-OCH₃, 8-OCH₃ F101.007 01 iso-butyl Ph— 7-methyl 02 iso-butyl Ph— 7-ethyl 03 iso-butyl Ph— 7-iso-propyl 04 iso-butyl Ph— 7-tert-butyl 05 iso-butyl Ph— 7-OH 06 iso-butyl Ph— 7-OCH₃ 07 iso-butyl Ph— 7-O(iso-propyl) 08 iso-butyl Ph— 7-SCH₃ 09 iso-butyl Ph— 7-SOCH₃ 10 iso-butyl Ph— 7-SO₂CH₃ 11 iso-butyl Ph— 7-SCH₂CH₃ 12 iso-butyl Ph— 7-NH₂ 13 iso-butyl Ph— 7-NHOH 14 iso-butyl Ph— 7-NHCH₃ 15 iso-butyl Ph— 7-N(CH₃)₂ 16 iso-butyl Ph— 7-N⁺(CH₃)₃, I⁻ 17 iso-butyl Ph— 7-NHC(═O)CH₃ 18 iso-butyl Ph— 7-N(CH₂CH₃)₂ 19 iso-butyl Ph— 7-NMeCH₂CO₂H 20 iso-butyl Ph— 7-N⁺(Me)₂CH₂CO₂H, I⁻ 21 iso-butyl Ph— 7-(N)-morpholine 22 iso-butyl Ph— 7-(N)-azetidine 23 iso-butyl Ph— 7-(N)-N-methylazetidinium, I⁻ 24 iso-butyl Ph— 7-(N)-pyrrolidine 25 iso-butyl Ph— 7-(N)-N-methyl-pyrrolidinium, I⁻ 26 iso-butyl Ph— 7-(N)-N-methyl-morpholinium, I⁻ 27 iso-butyl Ph— 7-(N)-N′-methylpiperazine 28 iso-butyl Ph— 7-(N)-N′-dimethylpiperazinium, I⁻ 29 iso-butyl Ph— 7-NH—CBZ 30 iso-butyl Ph— 7-NHC(O)C₅H₁₁ 31 iso-butyl Ph— 7-NHC(O)CH₂Br 32 iso-butyl Ph— 7-NH—C(NH)NH₂ 33 iso-butyl Ph— 7-(2)-thiophene 34 iso-butyl Ph— 8-methyl 35 iso-butyl Ph— 8-ethyl 36 iso-butyl Ph— 8-iso-propyl 37 iso-butyl Ph— 8-tert-butyl 38 iso-butyl Ph— 8-OH 39 iso-butyl Ph— 8-OCH₃ 40 iso-butyl Ph— 8-O(iso-propyl) 41 iso-butyl Ph— 8-SCH₃ 42 iso-butyl Ph— 8-SOCH₃ 43 iso-butyl Ph— 8-SO₂CH₃ 44 iso-butyl Ph— 8-SCH₂CH₃ 45 iso-butyl Ph— 8-NH₂ 46 iso-butyl Ph— 8-NHOH 47 iso-butyl Ph— 8-NHCH₃ 48 iso-butyl Ph— 8-N(CH₃)₂ 49 iso-butyl Ph— 8-N⁺(CH₃)₃, I⁻ 50 iso-butyl Ph— 8-NHC(═O)CH₃ 51 iso-butyl Ph— 8-N(CH₂CH₃)₂ 52 iso-butyl Ph— 8-NMeCH₂CO₂H 53 iso-butyl Ph— 8-N⁺(Me)₂CH₂CO₂H, I⁻ 54 iso-butyl Ph— 8-(N)-morpholine 55 iso-butyl Ph— 8-(N)-azetidine 56 iso-butyl Ph— 8-(N)-N-methylazetidinium, I⁻ 57 iso-butyl Ph— 8-(N)-pyrrolidine 58 iso-butyl Ph— 8-(N)-N-methyl-pyrrolidinium, I ⁻ 59 iso-butyl Ph— 8-(N)-N-methyl-morpholinium, I⁻ 60 iso-butyl Ph— 8-(N)-N′-methylpiperazine 61 iso-butyl Ph— 8-(N)-N′-dimethylpiperazinium, I⁻ 62 iso-butyl Ph— 8-NH—CBZ 63 iso-butyl Ph— 8-NHC(O)C₅H₁₁ 64 iso-butyl Ph— 8-NHC(O)CH₂Br 65 iso-butyl Ph— 8-NH—C(NH)NH₂ 66 iso-butyl Ph— 8-(2)-thiophene 67 iso-butyl Ph— 9-methyl 68 iso-butyl Ph— 9-ethyl 69 iso-butyl Ph— 9-iso-propyl 70 iso-butyl Ph— 9-tert-butyl 71 iso-butyl Ph— 9-OH 72 iso-butyl Ph— 9-OCH₃ 73 iso-butyl Ph— 9-O(iso-propyl) 74 iso-butyl Ph— 9-SCH₃ 75 iso-butyl Ph— 9-SOCH₃ 76 iso-butyl Ph— 9-SO₂CH₃ 77 iso-butyl Ph— 9-SCH₂CH₃ 78 iso-butyl Ph— 9-NH₂ 79 iso-butyl Ph— 9-NHOH 80 iso-butyl Ph— 9-NHCH₃ 81 iso-butyl Ph— 9-N(CH₃)₂ 82 iso-butyl Ph— 9-N⁺(CH₃)₃, I⁻ 83 iso-butyl Ph— 9-NHC(═O)CH₃ 84 iso-butyl Ph— 9-N(CH₂CH₃)₂ 85 iso-butyl Ph— 9-NMeCH₂CO₂H 86 iso-butyl Ph— 9-N⁺(Me)₂CH₂CO₂H, I⁻ 87 iso-butyl Ph— 9-(N)-morpholine 88 iso-butyl Ph— 9-(N)-azetidine 89 iso-butyl Ph— 9-(N)-N-methylazetidinium, I⁻ 90 iso-butyl Ph— 9-(N)-pyrrolidine 91 iso-butyl Ph— 9-(N)-N-methyl-pyrrolidinium, I⁻ 92 iso-butyl Ph— 9-(N)-N-methyl-morpholinium, I⁻ 93 iso-butyl Ph— 9-(N)-N′-methylpiperazine 93 iso-butyl Ph— 9-(N)-N′-dimethylpiperazinium, I⁻ 95 iso-butyl Ph— 9-NH—CBZ 96 iso-butyl Ph— 9-NHC(O)C₅H₁₁ 97 iso-butyl Ph— 9-NHC(O)CH₂Br 98 iso-butyl Ph— 9-NH—C(NH)NH₂ 99 iso-butyl Ph— 9-(2)-thiophene 100 iso-butyl Ph— 7-OCH₃, 8-OCH₃ 101 iso-butyl Ph— 7-SCH₃, 8-OCH₃ 102 iso-butyl Ph— 7-SCH₃, 8-SCH₃ 103 iso-butyl Ph— 6-OCH₃, 7-OCH₃, 8-OCH₃ F101.008 01 iso-pentyl Ph— 7-methyl 02 iso-pentyl Ph— 7-ethyl 03 iso-pentyl Ph— 7-iso-propyl 04 iso-pentyl Ph— 7-tert-butyl 05 iso-pentyl Ph— 7-OH 06 iso-pentyl Ph— 7-OCH₃ 07 iso-pentyl Ph— 7-O(iso-propyl) 08 iso-pentyl Ph— 7-SCH₃ 09 iso-pentyl Ph— 7-SOCH₃ 10 iso-pentyl Ph— 7-SO₂CH₃ 11 iso-pentyl Ph— 7-SCH₂CH₃ 12 iso-pentyl Ph— 7-NH₂ 13 iso-pentyl Ph— 7-NHOH 14 iso-pentyl Ph— 7-NHCH₃ 15 iso-pentyl Ph— 7-N(CH₃)₂ 16 iso-pentyl Ph— 7-N⁺(CH₃)₃, I⁻ 17 iso-pentyl Ph— 7-NHC(═O)CH₃ 18 iso-pentyl Ph— 7-N(CH₂CH₃)₂ 19 iso-pentyl Ph— 7-NMeCH₂CO₂H 20 iso-pentyl Ph— 7-N⁺(Me)₂CH₂CO₂H, I⁻ 21 iso-pentyl Ph— 7-(N)-morpholine 22 iso-pentyl Ph— 7-(N)-azetidine 23 iso-pentyl Ph— 7-(N)-N-methylazetidinium, I⁻ 24 iso-pentyl Ph— 7-(N)-pyrrolidine 25 iso-pentyl Ph— 7-(N)-N-methyl-pyrrolidinium, I⁻ 26 iso-pentyl Ph— 7-(N)-N-methyl-morpholinium, I⁻ 27 iso-pentyl Ph— 7-(N)-N′-methylpiperazine 28 iso-pentyl Ph— 7-(N)-N′-dimethylpiperazinium, I⁻ 29 iso-pentyl Ph— 7-NH—CBZ 30 iso-pentyl Ph— 7-NHC(O)C₅H₁₁ 31 iso-pentyl Ph— 7-NHC(O)CH₂Br 32 iso-pentyl Ph— 7-NH—C(NH)NH₂ 33 iso-pentyl Ph— 7-(2)-thiophene 34 iso-pentyl Ph— 8-methyl 35 iso-pentyl Ph— 8-ethyl 36 iso-pentyl Ph— 8-iso-propyl 37 iso-pentyl Ph— 8-tert-butyl 38 iso-pentyl Ph— 8-OH 39 iso-pentyl Ph— 8-OCH₃ 40 iso-pentyl Ph— 8-O(iso-propyl) 41 iso-pentyl Ph— 8-SCH₃ 42 iso-pentyl Ph— 8-SOCH₃ 43 iso-pentyl Ph— 8-SO₂CH₃ 44 iso-pentyl Ph— 8-SCH₂CH₃ 45 iso-pentyl Ph— 8-NH₂ 46 iso-pentyl Ph— 8-NHOH 47 iso-pentyl Ph— 8-NHCH₃ 48 iso-pentyl Ph— 8-N(CH₃)₂ 49 iso-pentyl Ph— 8-N⁺(CH₃)₃, I⁻ 50 iso-pentyl Ph— 8-NHC(═O)CH₃ 51 iso-pentyl Ph— 8-N(CH₂CH₃)₂ 52 iso-pentyl Ph— 8-NMeCH₂CO₂H 53 iso-pentyl Ph— 8-N⁺(Me)₂CH₂CO₂H, I⁻ 54 iso-pentyl Ph— 8-(N)-morpholine 55 iso-pentyl Ph— 8-(N)-azetidine 56 iso-pentyl Ph— 8-(N)-N-methylazetidinium, I⁻ 57 iso-pentyl Ph— 8-(N)-pyrrolidine 58 iso-pentyl Ph— 8-(N)-N-methyl-pyrrolidinium, I ⁻ 59 iso-pentyl Ph— 8-(N)-N-methyl-morpholinium, I⁻ 60 iso-pentyl Ph— 8-(N)-N′-methylpiperazine 61 iso-pentyl Ph— 8-(N)-N′-dimethylpiperazinium, I⁻ 62 iso-pentyl Ph— 8-NH—CBZ 63 iso-pentyl Ph— 8-NHC(O)C₅H₁₁ 64 iso-pentyl Ph— 8-NHC(O)CH₂Br 65 iso-pentyl Ph— 8-NH—C(NH)NH₂ 66 iso-pentyl Ph— 8-(2)-thiophene 67 iso-pentyl Ph— 9-methyl 68 iso-pentyl Ph— 9-ethyl 69 iso-pentyl Ph— 9-iso-propyl 70 iso-pentyl Ph— 9-tert-butyl 71 iso-pentyl Ph— 9-OH 72 iso-pentyl Ph— 9-OCH₃ 73 iso-pentyl Ph— 9-O(iso-propyl) 74 iso-pentyl Ph— 9-SCH₃ 75 iso-pentyl Ph— 9-SOCH₃ 76 iso-pentyl Ph— 9-SO₂CH₃ 77 iso-pentyl Ph— 9-SCH₂CH₃ 78 iso-pentyl Ph— 9-NH₂ 79 iso-pentyl Ph— 9-NHOH 80 iso-pentyl Ph— 9-NHCH₃ 81 iso-pentyl Ph— 9-N(CH₃)₂ 82 iso-pentyl Ph— 9-N⁺(CH₃)₃, I⁻ 83 iso-pentyl Ph— 9-NHC(═O)CH₃ 84 iso-pentyl Ph— 9-N(CH₂CH₃)₂ 85 iso-pentyl Ph— 9-NMeCH₂CO₂H 86 iso-pentyl Ph— 9-N⁺(Me)₂CH₂CO₂H, I⁻ 87 iso-pentyl Ph— 9-(N)-morpholine 88 iso-pentyl Ph— 9-(N)-azetidine 89 iso-pentyl Ph— 9-(N)-N-methylazetidinium, I⁻ 90 iso-pentyl Ph— 9-(N)-pyrrolidine 91 iso-pentyl Ph— 9-(N)-N-methyl-pyrrolidinium, I⁻ 92 iso-pentyl Ph— 9-(N)-N-methyl-morpholinium, I⁻ 93 iso-pentyl Ph— 9-(N)-N′-methylpiperazine 93 iso-pentyl Ph— 9-(N)-N′-dimethylpiperazinium, I⁻ 95 iso-pentyl Ph— 9-NH—CBZ 96 iso-pentyl Ph— 9-NHC(O)C₅H₁₁ 97 iso-pentyl Ph— 9-NHC(O)CH₂Br 98 iso-pentyl Ph— 9-NH—C(NH)NH₂ 99 iso-pentyl Ph— 9-(2)-thiophene 100 iso-pentyl Ph— 7-OCH₃, 8-OCH₃ 101 iso-pentyl Ph— 7-SCH₃, 8-OCH₃ 102 iso-pentyl Ph— 7-SCH₃, 8-SCH₃ 103 iso-pentyl Ph— 6-OCH₃, 7-OCH₃, 8-OCH₃ F101.009 01 CH₂C(═O)C₂H₅ Ph— 7-methyl 02 CH₂C(═O)C₂H₅ Ph— 7-ethyl 03 CH₂C(═O)C₂H₅ Ph— 7-iso-propyl 04 CH₂C(═O)C₂H₅ Ph— 7-tert-butyl 05 CH₂C(═O)C₂H₅ Ph— 7-OH 06 CH₂C(═O)C₂H₅ Ph— 7-OCH₃ 07 CH₂C(═O)C₂H₅ Ph— 7-O(iso-propyl) 08 CH₂C(═O)C₂H₅ Ph— 7-SCH₃ 09 CH_(2C(═O)C) ₂H₅ Ph— 7-SOCH₃ 10 CH₂C(═O)C₂H₅ Ph— 7-SO₂CH₃ 11 CH₂C(═O)C₂H₅ Ph— 7-SCH₂CH₃ 12 CH₂C(═O)C₂H₅ Ph— 7-NH₂ 13 CH₂C(═O)C₂H₅ Ph— 7-NHOH 14 CH₂C(═O)C₂H₅ Ph— 7-NHCH₃ 15 CH₂C(═O)C₂H₅ Ph— 7-N(CH₃)₂ 16 CH₂C(═O)C₂H₅ Ph— 7-N⁺(CH₃)₃, I⁻ 17 CH₂C(═O)C₂H₅ Ph— 7-NHC(═O)CH₃ 18 CH₂C(═O)C₂H₅ Ph— 7-N(CH₂CH₃)₂ 19 CH₂C(═O)C₂H₅ Ph— 7-NMeCH₂CO₂H 20 CH₂C(═O)C₂H₅ Ph— 7-N⁺(Me)₂CH₂CO₂H, I⁻ 21 CH₂C(═O)C₂H₅ Ph— 7-(N)-morpholine 22 CH₂C(═O)C₂H₅ Ph— 7-(N)-azetidine 23 CH₂C(═O)C₂H₅ Ph— 7-(N)-N-methylazetidinium, I⁻ 24 CH₂C(═O)C₂H₅ Ph— 7-(N)-pyrrolidine 25 CH₂C(═O)C₂H₅ Ph— 7-(N)-N-methyl-pyrrolidinium, I⁻ 26 CH₂C(═O)C₂H₅ Ph— 7-(N)-N-methyl-morpholinium, I⁻ 27 CH₂C(═O)C₂H₅ Ph— 7-(N)-N′-methylpiperazine 28 CH₂C(═O)C₂H₅ Ph— 7-(N)-N′-dimethylpiperazinium, I⁻ 29 CH₂C(═O)C₂H₅ Ph— 7-NH—CBZ 30 CH₂C(═O)C₂H₅ Ph— 7-NHC(O)C₅H₁₁ 31 CH₂C(═O)C₂H₅ Ph— 7-NHC(O)CH₂Br 32 CH₂C(═O)C₂H₅ Ph— 7-NH—C(NH)NH₂ 33 CH₂C(═O)C₂H₅ Ph— 7-(2)-thiophene 34 CH₂C(═O)C₂H₅ Ph— 8-methyl 35 CH₂C(═O)C₂H₅ Ph— 8-ethyl 36 CH₂C(═O)C₂H₅ Ph— 8-iso-propyl 37 CH₂C(═O)C₂H₅ Ph— 8-tert-butyl 38 CH₂C(═O)C₂H₅ Ph— 8-OH 39 CH₂C(═O)C₂H₅ Ph— 8-OCH₃ 40 CH₂C(═O)C₂H₅ Ph— 8-O(iso-propyl) 41 CH₂C(═O)C₂H₅ Ph— 8-SCH₃ 42 CH₂C(═O)C₂H₅ Ph— 8-SOCH₃ 43 CH₂C(═O)C₂H₅ Ph— 8-SO₂CH₃ 44 CH₂C(═O)C₂H₅ Ph— 8-SCH₂CH₃ 45 CH₂C(═O)C₂H₅ Ph— 8-NH₂ 46 CH₂C(═O)C₂H₅ Ph— 8-NHOH 47 CH₂C(═O)C₂H₅ Ph— 8-NHCH₃ 48 CH₂C(═O)C₂H₅ Ph— 8-N(CH₃)₂ 49 CH₂C(═O)C₂H₅ Ph— 8-N⁺(CH₃)₃, I⁻ 50 CH₂C(═O)C₂H₅ Ph— 8-NHC(═O)CH₃ 51 CH₂C(═O)C₂H₅ Ph— 8-N(CH₂CH₃)₂ 52 CH₂C(═O)C₂H₅ Ph— 8-NMeCH₂CO₂H 53 CH₂C(═O)C₂H₅ Ph— 8-N⁺(Me)₂CH₂CO₂H, I⁻ 54 CH₂C(═O)C₂H₅ Ph— 8-(N)-morpholine 55 CH₂C(═O)C₂H₅ Ph— 8-(N)-azetidine 56 CH₂C(═O)C₂H₅ Ph— 8-(N)-N-methylazetidinium, I⁻ 57 CH₂C(═O)C₂H₅ Ph— 8-(N)-pyrrolidine 58 CH₂C(═O)C₂H₅ Ph— 8-(N)-N-methyl-pyrrolidinium, I ⁻ 59 CH₂C(═O)C₂H₅ Ph— 8-(N)-N-methyl-morpholinium, I⁻ 60 CH₂C(═O)C₂H₅ Ph— 8-(N)-N′-methylpiperazine 61 CH₂C(═O)C₂H₅ Ph— 8-(N)-N′-dimethylpiperazinium, I⁻ 62 CH₂C(═O)C₂H₅ Ph— 8-NH—CBZ 63 CH₂C(═O)C₂H₅ Ph— 8-NHC(O)C₅H₁₁ 64 CH₂C(═O)C₂H₅ Ph— 8-NHC(O)CH₂Br 65 CH₂C(═O)C₂H₅ Ph— 8-NH—C(NH)NH₂ 66 CH₂C(═O)C₂H₅ Ph— 8-(2)-thiophene 67 CH₂C(═O)C₂H₅ Ph— 9-methyl 68 CH₂C(═O)C₂H₅ Ph— 9-ethyl 69 CH₂C(═O)C₂H₅ Ph— 9-iso-propyl 70 CH₂C(═O)C₂H₅ Ph— 9-tert-butyl 71 CH₂C(═O)C₂H₅ Ph— 9-OH 72 CH₂C(═O)C₂H₅ Ph— 9-OCH₃ 73 CH₂C(═O)C₂H₅ Ph— 9-O(iso-propyl) 74 CH₂C(═O)C₂H₅ Ph— 9-SCH₃ 75 CH₂C(═O)C₂H₅ Ph— 9-SOCH₃ 76 CH₂C(═O)C₂H₅ Ph— 9-SO₂CH₃ 77 CH₂C(═O)C₂H₅ Ph— 9-SCH₂CH₃ 78 CH₂C(═O)C₂H₅ Ph— 9-NH₂ 79 CH₂C(═O)C₂H₅ Ph— 9-NHOH 80 CH₂C(═O)C₂H₅ Ph— 9-NHCH₃ 81 CH₂C(═O)C₂H₅ Ph— 9-N(CH₃)₂ 82 CH₂C(═O)C₂H₅ Ph— 9-N⁺(CH₃)₃, I⁻ 83 CH₂C(═O)C₂H₅ Ph— 9-NHC(═O)CH₃ 84 CH₂C(═O)C₂H₅ Ph— 9-N(CH₂CH₃)₂ 85 CH₂C(═O)C₂H₅ Ph— 9-NMeCH₂CO₂H 86 CH₂C(═O)C₂H₅ Ph— 9-N⁺(Me)₂CH₂CO₂H, I⁻ 87 CH₂C(═O)C₂H₅ Ph— 9-(N)-morpholine 88 CH₂C(═O)C₂H₅ Ph— 9-(N)-azetidine 89 CH₂C(═O)C₂H₅ Ph— 9-(N)-N-methylazetidinium, I⁻ 90 CH₂C(═O)C₂H₅ Ph— 9-(N)-pyrrolidine 91 CH₂C(═O)C₂H₅ Ph— 9-(N)-N-methyl-pyrrolidinium, I⁻ 92 CH₂C(═O)C₂H₅ Ph— 9-(N)-N-methyl-morpholinium, I⁻ 93 CH₂C(═O)C₂H₅ Ph— 9-(N)-N′-methylpiperazine 93 CH₂C(═O)C₂H₅ Ph— 9-(N)-N′-dimethylpiperazinium, I⁻ 95 CH₂C(═O)C₂H₅ Ph— 9-NH—CBZ 96 CH₂C(═O)C₂H₅ Ph— 9-NHC(O)C₅H₁₁ 97 CH₂C(═O)C₂H₅ Ph— 9-NHC(O)CH₂Br 98 CH₂C(═O)C₂H₅ Ph— 9-NH—C(NH)NH₂ 99 CH₂C(═O)C₂H₅ Ph— 9-(2)-thiophene 100 CH₂C(═O)C₂H₅ Ph— 7-OCH₃, 8-OCH₃ 101 CH₂C(═O)C₂H₅ Ph— 7-SCH₃, 8-OCH₃ 102 CH₂C(═O)C₂H₅ Ph— 7-SCH₃, 8-SCH₃ 103 CH₂C(═O)C₂H₅ Ph— 6-OCH₃, 7-OCH₃, 8-OCH₃ F101.010 01 CH₂OC₂H₅ Ph— 7-methyl 02 CH₂OC₂H₅ Ph— 7-ethyl 03 CH₂OC₂H₅ Ph— 7-iso-propyl 04 CH₂OC₂H₅ Ph— 7-tert-butyl 05 CH₂OC₂H₅ Ph— 7-OH 06 CH₂OC₂H₅ Ph— 7-OCH₃ 07 CH₂OC₂H₅ Ph— 7-O(iso-propyl) 08 CH₂OC₂H₅ Ph— 7-SCH₃ 09 CH₂OC₂H₅ Ph— 7-SOCH₃ 10 CH₂OC₂H₅ Ph— 7-SO₂CH₃ 11 CH₂OC₂H₅ Ph— 7-SCH₂CH₃ 12 CH₂OC₂H₅ Ph— 7-NH₂ 13 CH₂OC₂H₅ Ph— 7-NHOH 14 CH₂OC₂H₅ Ph— 7-NHCH₃ 15 CH₂OC₂H₅ Ph— 7-N(CH₃)₂ 16 CH₂OC₂H₅ Ph— 7-N⁺(CH₃)₃, I⁻ 17 CH₂OC₂H₅ Ph— 7-NHC(═O)CH₃ 18 CH₂OC₂H₅ Ph— 7-N(CH₂CH₃)₂ 19 CH₂OC₂H₅ Ph— 7-NMeCH₂CO₂H 20 CH₂OC₂H₅ Ph— 7-N⁺(Me)₂CH₂CO₂H, I⁻ 21 CH₂OC₂H₅ Ph— 7-(N)-morpholine 22 CH₂OC₂H₅ Ph— 7-(N)-azetidine 23 CH₂OC₂H₅ Ph— 7-(N)-N-methylazetidinium, I⁻ 24 CH₂OC₂H₅ Ph— 7-(N)-pyrrolidine 25 CH₂OC₂H₅ Ph— 7-(N)-N-methyl-pyrrolidinium, I⁻ 26 CH₂OC₂H₅ Ph— 7-(N)-N-methyl-morpholinium, I⁻ 27 CH₂OC₂H₅ Ph— 7-(N)-N′-methylpiperazine 28 CH₂OC₂H₅ Ph— 7-(N)-N′-dimethylpiperazinium, I⁻ 29 CH₂OC₂H₅ Ph— 7-NH—CBZ 30 CH₂OC₂H₅ Ph— 7-NHC(O)C₅H₁₁ 31 CH₂OC₂H₅ Ph— 7-NHC(O)CH₂Br 32 CH₂OC₂H₅ Ph— 7-NH—C(NH)NH₂ 33 CH₂OC₂H₅ Ph— 7-(2)-thiophene 34 CH₂OC₂H₅ Ph— 8-methyl 35 CH₂OC₂H₅ Ph— 8-ethyl 36 CH₂OC₂H₅ Ph— 8-iso-propyl 37 CH₂OC₂H₅ Ph— 8-tert-butyl 38 CH₂OC₂H₅ Ph— 8-OH 39 CH₂OC₂H₅ Ph— 8-OCH₃ 40 CH₂OC₂H₅ Ph— 8-O(iso-propyl) 41 CH₂OC₂H₅ Ph— 8-SCH₃ 42 CH₂OC₂H₅ Ph— 8-SOCH₃ 43 CH₂OC₂H₅ Ph— 8-SO₂CH₃ 44 CH₂OC₂H₅ Ph— 8-SCH₂CH₃ 45 CH₂OC₂H₅ Ph— 8-NH₂ 46 CH₂OC₂H₅ Ph— 8-NHOH 47 CH₂OC₂H₅ Ph— 8-NHCH₃ 48 CH₂OC₂H₅ Ph— 8-N(CH₃)₂ 49 CH₂OC₂H₅ Ph— 8-N⁺(CH₃)₃, I⁻ 50 CH₂OC₂H₅ Ph— 8-NHC(═O)CH₃ 51 CH₂OC₂H₅ Ph— 8-N(CH₂CH₃)₂ 52 CH₂OC₂H₅ Ph— 8-NMeCH₂CO₂H 53 CH₂OC₂H₅ Ph— 8-N⁺(Me)₂CH₂CO₂H, I⁻ 54 CH₂OC₂H₅ Ph— 8-(N)-morpholine 55 CH₂OC₂H₅ Ph— 8-(N)-azetidine 56 CH₂OC₂H₅ Ph— 8-(N)-N-methylazetidinium, I⁻ 57 CH₂OC₂H₅ Ph— 8-(N)-pyrrolidine 58 CH₂OC₂H₅ Ph— 8-(N)-N-methyl-pyrrolidinium, I ⁻ 59 CH₂OC₂H₅ Ph— 8-(N)-N-methyl-morpholinium, I⁻ 60 CH₂OC₂H₅ Ph— 8-(N)-N′-methylpiperazine 61 CH₂OC₂H₅ Ph— 8-(N)-N′-dimethylpiperazinium, I⁻ 62 CH₂OC₂H₅ Ph— 8-NH—CBZ 63 CH₂OC₂H₅ Ph— 8-NHC(O)C₅H₁₁ 64 CH₂OC₂H₅ Ph— 8-NHC(O)CH₂Br 65 CH₂OC₂H₅ Ph— 8-NH—C(NH)NH₂ 66 CH₂OC₂H₅ Ph— 8-(2)-thiophene 67 CH₂OC₂H₅ Ph— 9-methyl 68 CH₂OC₂H₅ Ph— 9-ethyl 69 CH₂OC₂H₅ Ph— 9-iso-propyl 70 CH₂OC₂H₅ Ph— 9-tert-butyl 71 CH₂OC₂H₅ Ph— 9-OH 72 CH₂OC₂H₅ Ph— 9-OCH₃ 73 CH₂OC₂H₅ Ph— 9-O(iso-propyl) 74 CH₂OC₂H₅ Ph— 9-SCH₃ 75 CH₂OC₂H₅ Ph— 9-SOCH₃ 76 CH₂OC₂H₅ Ph— 9-SO₂CH₃ 77 CH₂OC₂H₅ Ph— 9-SCH₂CH₃ 78 CH₂OC₂H₅ Ph— 9-NH₂ 79 CH₂OC₂H₅ Ph— 9-NHOH 80 CH₂OC₂H₅ Ph— 9-NHCH₃ 81 CH₂OC₂H₅ Ph— 9-N(CH₃)₂ 82 CH₂OC₂H₅ Ph— 9-N⁺(CH₃)₃, I⁻ 83 CH₂OC₂H₅ Ph— 9-NHC(═O)CH₃ 84 CH₂OC₂H₅ Ph— 9-N(CH₂CH₃)₂ 85 CH₂OC₂H₅ Ph— 9-NMeCH₂CO₂H 86 CH₂OC₂H₅ Ph— 9-N⁺(Me)₂CH₂CO₂H, I⁻ 87 CH₂OC₂H₅ Ph— 9-(N)-morpholine 88 CH₂OC₂H₅ Ph— 9-(N)-azetidine 89 CH₂OC₂H₅ Ph— 9-(N)-N-methylazetidinium, I⁻ 90 CH₂OC₂H₅ Ph— 9-(N)-pyrrolidine 91 CH₂OC₂H₅ Ph— 9-(N)-N-methyl-pyrrolidinium, I⁻ 92 CH₂OC₂H₅ Ph— 9-(N)-N-methyl-morpholinium, I⁻ 93 CH₂OC₂H₅ Ph— 9-(N)-N′-methylpiperazine 93 CH₂OC₂H₅ Ph— 9-(N)-N′-dimethylpiperazinium, I⁻ 95 CH₂OC₂H₅ Ph— 9-NH—CBZ 96 CH₂OC₂H₅ Ph— 9-NHC(O)C₅H₁₁ 97 CH₂OC₂H₅ Ph— 9-NHC(O)CH₂Br 98 CH₂OC₂H₅ Ph— 9-NH—C(NH)NH₂ 99 CH₂OC₂H₅ Ph— 9-(2)-thiophene 100 CH₂OC₂H₅ Ph— 7-OCH₃, 8-OCH₃ 101 CH₂OC₂H₅ Ph— 7-SCH₃, 8-OCH₃ 102 CH₂OC₂H₅ Ph— 7-SCH₃, 8-SCH₃ 103 CH₂OC₂H₅ Ph— 6-OCH₃, 7-OCH₃, 8-OCH₃ F101.011 01 CH₂CH(OH)C₂H₅ Ph— 7-methyl 02 CH₂CH(OH)C₂H₅ Ph— 7-ethyl 03 CH₂CH(OH)C₂H₅ Ph— 7-iso-propyl 04 CH₂CH(OH)C₂H₅ Ph— 7-tert-butyl 05 CH₂CH(OH)C₂H₅ Ph— 7-OH 06 CH₂CH(OH)C₂H₅ Ph— 7-OCH₃ 07 CH₂CH(OH)C₂H₅ Ph— 7-O(iso-propyl) 08 CH₂CH(OH)C₂H₅ Ph— 7-SCH₃ 09 CH₂CH(OH)C₂H₅ Ph— 7-SOCH₃ 10 CH₂CH(OH)C₂H₅ Ph— 7-SO₂CH₃ 11 CH₂CH(OH)C₂H₅ Ph— 7-SCH₂CH₃ 12 CH₂CH(OH)C₂H₅ Ph— 7-NH₂ 13 CH₂CH(OH)C₂H₅ Ph— 7-NHOH 14 CH₂CH(OH)C₂H₅ Ph— 7-NHCH₃ 15 CH₂CH(OH)C₂H₅ Ph— 7-N(CH₃)₂ 16 CH₂CH(OH)C₂H₅ Ph— 7-N⁺(CH₃)₃, I⁻ 17 CH₂CH(OH)C₂H₅ Ph— 7-NHC(═O)CH₃ 18 CH₂CH(OH)C₂H₅ Ph— 7-N(CH₂CH₃)₂ 19 CH₂CH(OH)C₂H₅ Ph— 7-NMeCH₂CO₂H 20 CH₂CH(OH)C₂H₅ Ph— 7-N⁺(Me)₂CH₂CO₂H, I⁻ 21 CH₂CH(OH)C₂H₅ Ph— 7-(N)-morpholine 22 CH₂CH(OH)C₂H₅ Ph— 7-(N)-azetidine 23 CH₂CH(OH)C₂H₅ Ph— 7-(N)-N-methylazetidinium, I⁻ 24 CH₂CH(OH)C₂H₅ Ph— 7-(N)-pyrrolidine 25 CH₂CH(OH)C₂H₅ Ph— 7-(N)-N-methyl-pyrrolidinium, I⁻ 26 CH₂CH(OH)C₂H₅ Ph— 7-(N)-N-methyl-morpholinium, I⁻ 27 CH₂CH(OH)C₂H₅ Ph— 7-(N)-N′-methylpiperazine 28 CH₂CH(OH)C₂H₅ Ph— 7-(N)-N′-dimethylpiperazinium, I⁻ 29 CH₂CH(OH)C₂H₅ Ph— 7-NH—CBZ 30 CH₂CH(OH)C₂H₅ Ph— 7-NHC(O)C₅H₁₁ 31 CH₂CH(OH)C₂H₅ Ph— 7-NHC(O)CH₂Br 32 CH₂CH(OH)C₂H₅ Ph— 7-NH—C(NH)NH₂ 33 CH₂CH(OH)C₂H₅ Ph— 7-(2)-thiophene 34 CH₂CH(OH)C₂H₅ Ph— 8-methyl 35 CH₂CH(OH)C₂H₅ Ph— 8-ethyl 36 CH₂CH(OH)C₂H₅ Ph— 8-iso-propyl 37 CH₂CH(OH)C₂H₅ Ph— 8-tert-butyl 38 CH₂CH(OH)C₂H₅ Ph— 8-OH 39 CH₂CH(OH)C₂H₅ Ph— 8-OCH₃ 40 CH₂CH(OH)C₂H₅ Ph— 8-O(iso-propyl) 41 CH₂CH(OH)C₂H₅ Ph— 8-SCH₃ 42 CH₂CH(OH)C₂H₅ Ph— 8-SOCH₃ 43 CH₂CH(OH)C₂H₅ Ph— 8-SO₂CH₃ 44 CH₂CH(OH)C₂H₅ Ph— 8-SCH₂CH₃ 45 CH₂CH(OH)C₂H₅ Ph— 8-NH₂ 46 CH₂CH(OH)C₂H₅ Ph— 8-NHOH 47 CH₂CH(OH)C₂H₅ Ph— 8-NHCH₃ 48 CH₂CH(OH)C₂H₅ Ph— 8-N(CH₃)₂ 49 CH₂CH(OH)C₂H₅ Ph— 8-N⁺(CH₃)₃, I⁻ 50 CH₂CH(OH)C₂H₅ Ph— 8-NHC(═O)CH₃ 51 CH₂CH(OH)C₂H₅ Ph— 8-N(CH₂CH₃)₂ 52 CH₂CH(OH)C₂H₅ Ph— 8-NMeCH₂CO₂H 53 CH₂CH(OH)C₂H₅ Ph— 8-N⁺(Me)₂CH₂CO₂H, I⁻ 54 CH₂CH(OH)C₂H₅ Ph— 8-(N)-morpholine 55 CH₂CH(OH)C₂H₅ Ph— 8-(N)-azetidine 56 CH₂CH(OH)C₂H₅ Ph— 8-(N)-N-methylazetidinium, I⁻ 57 CH₂CH(OH)C₂H₅ Ph— 8-(N)-pyrrolidine 58 CH₂CH(OH)C₂H₅ Ph— 8-(N)-N-methyl-pyrrolidinium, I ⁻ 59 CH₂CH(OH)C₂H₅ Ph— 8-(N)-N-methyl-morpholinium, I⁻ 60 CH₂CH(OH)C₂H₅ Ph— 8-(N)-N′-methylpiperazine 61 CH₂CH(OH)C₂H₅ Ph— 8-(N)-N′-dimethylpiperazinium, I⁻ 62 CH₂CH(OH)C₂H₅ Ph— 8-NH—CBZ 63 CH₂CH(OH)C₂H₅ Ph— 8-NHC(O)C₅H₁₁ 64 CH₂CH(OH)C₂H₅ Ph— 8-NHC(O)CH₂Br 65 CH₂CH(OH)C₂H₅ Ph— 8-NH—C(NH)NH₂ 66 CH₂CH(OH)C₂H₅ Ph— 8-(2)-thiophene 67 CH₂CH(OH)C₂H₅ Ph— 9-methyl 68 CH₂CH(OH)C₂H₅ Ph— 9-ethyl 69 CH₂CH(OH)C₂H₅ Ph— 9-iso-propyl 70 CH₂CH(OH)C₂H₅ Ph— 9-tert-butyl 71 CH₂CH(OH)C₂H₅ Ph— 9-OH 72 CH₂CH(OH)C₂H₅ Ph— 9-OCH₃ 73 CH₂CH(OH)C₂H₅ Ph— 9-O(iso-propyl) 74 CH₂CH(OH)C₂H₅ Ph— 9-SCH₃ 75 CH₂CH(OH)C₂H₅ Ph— 9-SOCH₃ 76 CH₂CH(OH)C₂H₅ Ph— 9-SO₂CH₃ 77 CH₂CH(OH)C₂H₅ Ph— 9-SCH₂CH₃ 78 CH₂CH(OH)C₂H₅ Ph— 9-NH₂ 79 CH₂CH(OH)C₂H₅ Ph— 9-NHOH 80 CH₂CH(OH)C₂H₅ Ph— 9-NHCH₃ 81 CH₂CH(OH)C₂H₅ Ph— 9-N(CH₃)₂ 82 CH₂CH(OH)C₂H₅ Ph— 9-N⁺(CH₃)₃, I⁻ 83 CH₂CH(OH)C₂H₅ Ph— 9-NHC(═O)CH₃ 84 CH₂CH(OH)C₂H₅ Ph— 9-N(CH₂CH₃)₂ 85 CH₂CH(OH)C₂H₅ Ph— 9-NMeCH₂CO₂H 86 CH₂CH(OH)C₂H₅ Ph— 9-N⁺(Me)₂CH₂CO₂H, I⁻ 87 CH₂CH(OH)C₂H₅ Ph— 9-(N)-morpholine 88 CH₂CH(OH)C₂H₅ Ph— 9-(N)-azetidine 89 CH₂CH(OH)C₂H₅ Ph— 9-(N)-N-methylazetidinium, I⁻ 90 CH₂CH(OH)C₂H₅ Ph— 9-(N)-pyrrolidine 91 CH₂CH(OH)C₂H₅ Ph— 9-(N)-N-methyl-pyrrolidinium, I⁻ 92 CH₂CH(OH)C₂H₅ Ph— 9-(N)-N-methyl-morpholinium, I⁻ 93 CH₂CH(OH)C₂H₅ Ph— 9-(N)-N′-methylpiperazine 93 CH₂CH(OH)C₂H₅ Ph— 9-(N)-N′-dimethylpiperazinium, I⁻ 95 CH₂CH(OH)C₂H₅ Ph— 9-NH—CBZ 96 CH₂CH(OH)C₂H₅ Ph— 9-NHC(O)C₅H₁₁ 97 CH₂CH(OH)C₂H₅ Ph— 9-NHC(O)CH₂Br 98 CH₂CH(OH)C₂H₅ Ph— 9-NH—C(NH)NH₂ 99 CH₂CH(OH)C₂H₅ Ph— 9-(2)-thiophene 100 CH₂CH(OH)C₂H₅ Ph— 7-OCH₃, 8-OCH₃ 101 CH₂CH(OH)C₂H₅ Ph— 7-SCH₃, 8-OCH₃ 102 CH₂CH(OH)C₂H₅ Ph— 7-SCH₃, 8-SCH₃ 103 CH₂CH(OH)C₂H₅ Ph— 6-OCH₃, 7-OCH₃, 8-OCH₃ F101.012 01 CH₂O-(4-picoline) Ph— 7-methyl 02 CH₂O-(4-picoline) Ph— 7-ethyl 03 CH₂O-(4-picoline) Ph— 7-iso-propyl 04 CH₂O-(4-picoline) Ph— 7-tert-butyl 05 CH₂O-(4-picoline) Ph— 7-OH 06 CH₂O-(4-picoline) Ph— 7-OCH₃ 07 CH₂O-(4-picoline) Ph— 7-O(iso-propyl) 08 CH₂O-(4-picoline) Ph— 7-SCH₃ 09 CH₂O-(4-picoline) Ph— 7-SOCH₃ 10 CH₂O-(4-picoline) Ph— 7-SO₂CH₃ 11 CH₂O-(4-picoline) Ph— 7-SCH₂CH₃ 12 CH₂O-(4-picoline) Ph— 7-NH₂ 13 CH₂O-(4-picoline) Ph— 7-NHOH 14 CH₂O-(4-picoline) Ph— 7-NHCH₃ 15 CH₂O-(4-picoline) Ph— 7-N(CH₃)₂ 16 CH₂O-(4-picoline) Ph— 7-N⁺(CH₃)₃, I⁻ 17 CH₂O-(4-picoline) Ph— 7-NHC(═O)CH₃ 18 CH₂O-(4-picoline) Ph— 7-N(CH₂CH₃)₂ 19 CH₂O-(4-picoline) Ph— 7-NMeCH₂CO₂H 20 CH₂O-(4-picoline) Ph— 7-N⁺(Me)₂CH₂CO₂H, I⁻ 21 CH₂O-(4-picoline) Ph— 7-(N)-morpholine 22 CH₂O-(4-picoline) Ph— 7-(N)-azetidine 23 CH₂O-(4-picoline) Ph— 7-(N)-N-methylazetidinium, I⁻ 24 CH₂O-(4-picoline) Ph— 7-(N)-pyrrolidine 25 CH₂O-(4-picoline) Ph— 7-(N)-N-methyl-pyrrolidinium, I⁻ 26 CH₂O-(4-picoline) Ph— 7-(N)-N-methyl-morpholinium, I⁻ 27 CH₂O-(4-picoline) Ph— 7-(N)-N′-methylpiperazine 28 CH₂O-(4-picoline) Ph— 7-(N)-N′-dimethylpiperazinium, I⁻ 29 CH₂O-(4-picoline) Ph— 7-NH—CBZ 30 CH₂O-(4-picoline) Ph— 7-NHC(O)C₅H₁₁ 31 CH₂O-(4-picoline) Ph— 7-NHC(O)CH₂Br 32 CH₂O-(4-picoline) Ph— 7-NH—C(NH)NH₂ 33 CH₂O-(4-picoline) Ph— 7-(2)-thiophene 34 CH₂O-(4-picoline) Ph— 8-methyl 35 CH₂O-(4-picoline) Ph— 8-ethyl 36 CH₂O-(4-picoline) Ph— 8-iso-propyl 37 CH₂O-(4-picoline) Ph— 8-tert-butyl 38 CH₂O-(4-picoline) Ph— 8-OH 39 CH₂O-(4-picoline) Ph— 8-OCH₃ 40 CH₂O-(4-picoline) Ph— 8-O(iso-propyl) 41 CH₂O-(4-picoline) Ph— 8-SCH₃ 42 CH₂O-(4-picoline) Ph— 8-SOCH₃ 43 CH₂O-(4-picoline) Ph— 8-SO₂CH₃ 44 CH₂O-(4-picoline) Ph— 8-SCH₂CH₃ 45 CH₂O-(4-picoline) Ph— 8-NH₂ 46 CH₂O-(4-picoline) Ph— 8-NHOH 47 CH₂O-(4-picoline) Ph— 8-NHCH₃ 48 CH₂O-(4-picoline) Ph— 8-N(CH₃)₂ 49 CH₂O-(4-picoline) Ph— 8-N⁺(CH₃)₃, I⁻ 50 CH₂O-(4-picoline) Ph— 8-NHC(═O)CH₃ 51 CH₂O-(4-picoline) Ph— 8-N(CH₂CH₃)₂ 52 CH₂O-(4-picoline) Ph— 8-NMeCH₂CO₂H 53 CH₂O-(4-picoline) Ph— 8-N⁺(Me)₂CH₂CO₂H, I⁻ 54 CH₂O-(4-picoline) Ph— 8-(N)-morpholine 55 CH₂O-(4-picoline) Ph— 8-(N)-azetidine 56 CH₂O-(4-picoline) Ph— 8-(N)-N-methylazetidinium, I⁻ 57 CH₂O-(4-picoline) Ph— 8-(N)-pyrrolidine 58 CH₂O-(4-picoline) Ph— 8-(N)-N-methyl-pyrrolidinium, I ⁻ 59 CH₂O-(4-picoline) Ph— 8-(N)-N-methyl-morpholinium, I⁻ 60 CH₂O-(4-picoline) Ph— 8-(N)-N′-methylpiperazine 61 CH₂O-(4-picoline) Ph— 8-(N)-N′-dimethylpiperazinium, I⁻ 62 CH₂O-(4-picoline) Ph— 8-NH—CBZ 63 CH₂O-(4-picoline) Ph— 8-NHC(O)C₅H₁₁ 64 CH₂O-(4-picoline) Ph— 8-NHC(O)CH₂Br 65 CH₂O-(4-picoline) Ph— 8-NH—C(NH)NH₂ 66 CH₂O-(4-picoline) Ph— 8-(2)-thiophene 67 CH₂O-(4-picoline) Ph— 9-methyl 68 CH₂O-(4-picoline) Ph— 9-ethyl 69 CH₂O-(4-picoline) Ph— 9-iso-propyl 70 CH₂O-(4-picoline) Ph— 9-tert-butyl 71 CH₂O-(4-picoline) Ph— 9-OH 72 CH₂O-(4-picoline) Ph— 9-OCH₃ 73 CH₂O-(4-picoline) Ph— 9-O(iso-propyl) 74 CH₂O-(4-picoline) Ph— 9-SCH₃ 75 CH₂O-(4-picoline) Ph— 9-SOCH₃ 76 CH₂O-(4-picoline) Ph— 9-SO₂CH₃ 77 CH₂O-(4-picoline) Ph— 9-SCH₂CH₃ 78 CH₂O-(4-picoline) Ph— 9-NH₂ 79 CH₂O-(4-picoline) Ph— 9-NHOH 80 CH₂O-(4-picoline) Ph— 9-NHCH₃ 81 CH₂O-(4-picoline) Ph— 9-N(CH₃)₂ 82 CH₂O-(4-picoline) Ph— 9-N⁺(CH₃)₃, I⁻ 83 CH₂O-(4-picoline) Ph— 9-NHC(═O)CH₃ 84 CH₂O-(4-picoline) Ph— 9-N(CH₂CH₃)₂ 85 CH₂O-(4-picoline) Ph— 9-NMeCH₂CO₂H 86 CH₂O-(4-picoline) Ph— 9-N⁺(Me)₂CH₂CO₂H, I⁻ 87 CH₂O-(4-picoline) Ph— 9-(N)-morpholine 88 CH₂O-(4-picoline) Ph— 9-(N)-azetidine 89 CH₂O-(4-picoline) Ph— 9-(N)-N-methylazetidinium, I⁻ 90 CH₂O-(4-picoline) Ph— 9-(N)-pyrrolidine 91 CH₂O-(4-picoline) Ph— 9-(N)-N-methyl-pyrrolidinium, I⁻ 92 CH₂O-(4-picoline) Ph— 9-(N)-N-methyl-morpholinium, I⁻ 93 CH₂O-(4-picoline) Ph— 9-(N)-N′-methylpiperazine 93 CH₂O-(4-picoline) Ph— 9-(N)-N′-dimethylpiperazinium, I⁻ 95 CH₂O-(4-picoline) Ph— 9-NH—CBZ 96 CH₂O-(4-picoline) Ph— 9-NHC(O)C₅H₁₁ 97 CH₂O-(4-picoline) Ph— 9-NHC(O)CH₂Br 98 CH₂O-(4-picoline) Ph— 9-NH—C(NH)NH₂ 99 CH₂O-(4-picoline) Ph— 9-(2)-thiophene 100 CH₂O-(4-picoline) Ph— 7-OCH₃, 8-OCH₃ 101 CH₂O-(4-picoline) Ph— 7-SCH₃, 8-OCH₃ 102 CH₂O-(4-picoline) Ph— 7-SCH₃, 8-SCH₃ 103 CH₂O-(4-picoline) Ph— 6-OCH₃, 7-OCH₃, 8-OCH₃

Additional Structures of the Present Invention

Compound Number R¹ R² R³ R⁴ R⁵ R⁶ (R^(x))_(q) 101 ethyl n-butyl OH H phenyl H

102 ethyl n-butyl OH H phenyl H 7-trimethylammonium iodide 103 n-butyl ethyl OH H phenyl H 7-trimethylammonium iodide 104 ethyl n-butyl OH H phenyl H 7-dimethylamino 105 ethyl n-butyl OH H phenyl H 7-methanesulfonamido 106 ethyl n-butyl OH H phenyl H 7-(2′-bromoacetamido) 107 n-butyl ethyl OH H 4-(decyloxy)phenyl H 7-amino 108 ethyl n-butyl OH H phenyl H 7-(hexylamido) 109 ethyl n-butyl OH H 4-(decyloxy)phenyl H 7-amino 110 ethyl n-butyl OH H phenyl H 7-acetamido 111 n-butyl ethyl OH H 4-hydroxyphenyl H 7-amino 112 ethyl n-butyl OH H

H 7-amino 113 ethyl n-butyl OH H 4-hydroxyphenyl H 7-amino 114 ethyl n-butyl OH H 4-methoxyphenyl H 7-amino 115 n-butyl ethyl OH H 4-methoxyphenyl H 7-(0-benzylcarbamato) 116 ethyl n-butyl OH H 4-methoxyphenyl H 7-(0-benzylcarbamato) 117 n-butyl ethyl OH H phenyl H 7-(0-benzylcarbamato) 118 ethyl n-butyl OH H phenyl H 7-(0-benzylcarbamato) 119 ethyl n-butyl OH H phenyl H 7-(0-tert-butylcarbamato) 120 n-butyl ethyl OH H phenyl H 7-(0-benzylcarbamato) 121 ethyl n-butyl OH H phenyl H 7-amino 122 n-butyl ethyl OH H phenyl H 7-amino 123 ethyl n-butyl OH H phenyl H 7-hexylamino 124 n-butyl ethyl OH H phenyl H 7-(hexlamino) 125 ethyl n-butyl OH H phenyl H

126 n-butyl ethyl OH H 4-fluorophenyl H 7-(0-benzylcarbamato) 127 n-butyl ethyl OH H 4-fluorophenyl H 7-amino 128 ethyl n-butyl OH H 4-fluorophenyl H 7-(0-benzylcarbamato) 129 ethyl n-butyl OH H 4-fluorophenyl H 7-amino 131 ethyl n-butyl OH H 4-fluorophenyl H

132 ethyl n-butyl OH H phenyl H

133 ethyl n-butyl OH H phenyl H 8-(hexyloxy) 134 ethyl n-butyl OH H phenyl H

135 ethyl n-butyl OH H phenyl H

136 ethyl n-butyl OH H phenyl H 8-hydroxy 137 n-butyl ethyl OH H phenyl H

138 n-butyl ethyl OH H phenyl H 8-acetoxy 139 n-butyl ethyl OH H phenyl H

140 141 142 ethyl n-butyl H OH H 3-methoxy- 7-methylmercapto phenyl 143 ethyl n-butyl OH H 3-methoxyphenyl H 7-methylmercapto 144 ethyl n-butyl OH H 4-fluorophenyl H 7-(N-azetidinyl) 262 ethyl n-butyl OH H 3-methoxyphenyl H 7-methoxy 263 ethyl n-butyl H OH H 3-methoxy- 7-methoxy phenyl 264 ethyl n-butyl OH H 3-trifluoromethylphenyl H 7-methoxy 265 ethyl n-butyl H OH H 3- 7-methoxy trifluoro- methyl- phenyl 266 ethyl n-butyl OH H 3-hyfroxyphenyl H 7-hydroxy 267 ethyl n-butyl OH H 3-hydroxyphenyl H 7-methoxy 268 ethyl n-butyl OH H 4-fluorophenyl H 7-methoxy 269 ethyl n-butyl H OH H 4-fluoro- 7-methoxy phenyl 270 ethyl n-butyl OH H 4-fluorophenyl H 7-hydroxy 271 ethyl n-butyl OH H 3-methoxyphenyl H 7-bromo 272 ethyl n-butyl H OH H 3-methoxy- 7-bromo phenyl 273 ethyl n-butyl H OH H 4-fluoro- 7-fluoro phenyl 274 ethyl n-butyl OH H 4-fluorophenyl H 7-fluoro 275 ethyl n-butyl H OH H 3-methoxy- 7-fluoro phenyl 276 ethyl n-butyl OH H 3-methoxyphenyl H 7-fluoro 277 ethyl n-butyl OH H 3-fluorophenyl H 7-methoxy 278 ethyl n-butyl H OH 2-fluorophenyl H 7-methoxy 279 ethyl n-butyl H OH 3-fluorophenyl H 7-methoxy 280 ethyl n-butyl OH H 2-fluorophenyl H 7-methoxy 281 ethyl n-butyl OH H 4-fluorophenyl H 7-methylmercapto 282 ethyl n-butyl OH H 4-fluorophenyl H 7-methyl 283 ethyl n-butyl H OH H 4-fluoro- 7-methyl phenyl 284 ethyl n-butyl OH H 4-fluorophenyl H 7-(4′-merpholino) 286 ethyl ethyl OH H phenyl H 7-(0-benzylcarbamato) 287 ethyl ethyl OH H phenyl H 7-amino 288 methyl methyl OH H phenyl H 7-amino 289 n-butyl n-butyl OH H phenyl H 7-amino 290 n-butyl n-butyl OH H phenyl H 7-amino 291 n-butyl n-butyl OH H phenyl H 7-(0-benzylcarbamato) 292 n-butyl n-butyl OH H 4-fluorophenyl H 7-amino 293 n-butyl n-butyl OH H phenyl H 7-benzylamino 294 n-butyl n-butyl OH H phenyl H 7-dimethylamino 295 ethyl n-butyl OH H

H 7-amino 296 ethyl n-butyl OH H

H 7-amino 1000 ethyl n-butyl OH H

H 7-dimethylamino 1001 ethyl n-butyl OH H

H 7-dimethylamino 1002 ethyl n-butyl OH H

H 7-dimethylamino 1003 ethyl n-butyl OH H

H 7-dimethylamino 1004 ethyl n-butyl OH H

H 7-dimethylamino 1005 n-butyl n-butyl OH H

H 7-dimethylamino 1006 n-butyl n-butyl OH H

H 7-dimethylamino 1007 n-butyl n-butyl OH H

H 7-dimethylamino 1008 n-butyl n-butyl OH H

H 7-dimethylamino 1009 n-butyl n-butyl OH H

H 7-dimethylamino 1010 n-butyl n-butyl OH H 3-fluoro-4-methoxyphenyl H 7-dimethylamino 1011 n-butyl n-butyl OH H 3-fluoro-4-(5-triethylammoniumpentyloxy)phenyl, H 7-dimethylamino trifluoroacetate salt 1012 n-butyl n-butyl OH H 4-hydroxyphenyl H 7-dimethylamino; 9-methoxy 1013 n-butyl n-butyl OH H

H 7-dimethylamino 1014 n-butyl n-butyl OH H 4-methoxyphenyl H 7-dimethylamino; 9-methoxy 1015 n-butyl n-butyl OH H

H 7-dimethylamino 1016 n-butyl n-butyl OH H

H 7-dimethylamino 1017 n-butyl n-butyl OH H

H 7-dimethylamino 1018 n-butyl n-butyl OH H

H 7-dimethylamino 1019 n-butyl n-butyl OH H

H 7-dimethylamino 1020 n-butyl n-butyl OH H

H 7-dimethylamino 1021 n-butyl n-butyl OH H

H 7-dimethylamino 1022 n-butyl n-butyl OH H

H 7-dimethylamino 1023 n-butyl n-butyl OH H

H 7-dimethylamino 1024 n-butyl n-butyl OH H

H 7-dimethylamino 1025 n-butyl n-butyl OH H

H 7-dimethylamino 1026 n-butyl n-butyl OH H

H 7-dimethylamino 1027 n-butyl n-butyl OH H

H 7-dimethylamino 1028 n-butyl n-butyl OH H

H 7-dimethylamino 1029 n-butyl n-butyl OH H

H 7-dimethylamino 1030 n-butyl n-butyl OH H

H 7-dimethylamino 1031 n-butyl n-butyl OH H

H 7-dimethylamino 1032 n-butyl n-butyl OH H

H 7-dimethylamino 1033 n-butyl n-butyl OH H

H 7-dimethylamino 1034 n-butyl n-butyl OH H

H 7-dimethylamino 1035 n-butyl n-butyl OH H

H 7-dimethylamino 1036 n-butyl n-butyl OH H

H 7-dimethylamino 1037 n-butyl n-butyl OH H 4-hydroxyphenyl H 7-dimethylamino 1038 n-butyl n-butyl OH H

H 7-dimethylamino 1039 n-butyl n-butyl OH H phenyl H 7-dimethylamino 1040 n-butyl n-butyl OH H

H 7-dimethylamino 1041 n-butyl n-butyl OH H

H 7-dimethylamino 1042 n-butyl n-butyl OH H

H 7-dimethylamino 1043 n-butyl n-butyl OH H

H 7-dimethylamino 1044 n-butyl n-butyl OH H

H 7-dimethylamino 1045 n-butyl n-butyl OH H

H 7-dimethylamino 1046 n-butyl n-butyl OH H 3-aminophenyl H 7-dimethylamino 1047 n-butyl n-butyl OH H

H 7-dimethylamino 1048 n-butyl n-butyl OH H

H 7-dimethylamino 1049 n-butyl n-butyl OH H

H 7-dimethylamino 1050 n-butyl n-butyl OH H

H 7-dimethylamino 1051 n-butyl n-butyl OH H

H 7-dimethylamino 1052 n-butyl n-butyl OH H

H 7-dimethylamino 1053 n-butyl n-butyl OH H

H 7-dimethylamino 1054 n-butyl n-butyl OH H

H 7-dimethylamino 1055 n-butyl n-butyl OH H

H 7-dimethylamino 1056 n-butyl n-butyl OH H

H 7-dimethylamino 1057 n-butyl n-butyl OH H

H 7-dimethylamino 1058 n-butyl n-butyl OH H

H 7-dimethylamino 1059 n-butyl n-butyl OH H

H 7-dimethylamino 1060 ethyl n-butyl OH H 3-fluoro-4-methoxyphenyl H 7-methylamino 1061 n-butyl n-butyl OH H

H 7-methylamino 1062 n-butyl n-butyl OH H

H 7-methylamino 1063 n-butyl n-butyl OH H

H 7-methylamino 1064 n-butyl n-butyl OH H

H 7-methylamino 1065 n-butyl n-butyl OH H

H 7-dimethylamino 1066 n-butyl n-butyl OH H

H 7-dimethylamino 1067 n-butyl n-butyl OH H thiophen-3-yl H 9-dimethylamino 1068 n-butyl n-butyl OH H

H 7-dimethylamino 1069 n-butyl n-butyl OH H phenyl H 7-dimethylamino; 9-dimethylamino 1070 n-butyl n-butyl OH H

H 7-dimethylamino 1071 n-butyl n-butyl OH H

H 7-dimethylamino 1072 n-butyl n-butyl OH H

H 7-dimethylamino 1073 n-butyl n-butyl OH H

H 7-dimethylamino 1074 ethyl n-butyl OH H 3-fluoro-4-methoxyphenyl H 7-dimethylamino 1075 n-butyl n-butyl OH H 4-fluorophenyl H 7-dimethylamino; 9-dimethylamino 1076 n-butyl n-butyl OH H

H 7-dimethylamino 1077 n-butyl n-butyl OH H 3-hydroxymethylphenyl H 7-dimethylamino 1078 ethyl n-butyl OH H 4-hydroxyphenyl H 7-dimethylamino 1079 ethyl n-butyl OH H

H 7-dimethylamino 1080 n-butyl n-butyl OH H

H 7-dimethylamino 1081 n-butyl n-butyl OH H

H 7-dimethylamino 1082 n-butyl n-butyl OH H 2-pyridyl H 7-dimethylamino 1083 n-butyl n-butyl OH H

H 7-dimethylamino 1084 n-butyl n-butyl OH H

H 7-dimethylamino 1085 n-butyl n-butyl OH H thiophen-3-yl H 7-dimethylamino 1086 n-butyl n-butyl OH H

H 7-dimethylamino 1087 n-butyl n-butyl OH H

H 7-dimethylamino 1088 ethyl n-butyl OH H 3,4-methylenedioxyphenyl H 7-dimethylamino 1089 ethyl n-butyl OH H 4-methoxyphenyl 1090 n-butyl n-butyl OH H

H 7-dimethylamino 1091 n-butyl n-butyl OH H

H 7-dimethylamino 1092 n-butyl n-butyl OH H

H 7-dimethylamino 1093 n-butyl n-butyl OH H

H 7-dimethylamino 1094 n-butyl n-butyl OH H

H 7-dimethylamino 1095 n-butyl n-butyl OH H

H 7-dimethylamino 1096 n-butyl n-butyl OH H

H 7-dimethylamino 1097 n-butyl n-butyl OH H

H 7-dimethylamino 1098 n-butyl n-butyl OH H

H 7-dimethylamino 1099 ethyl n-butyl OH H 4-methoxyphenyl H 7-dimethylamino 1100 n-butyl n-butyl OH H 4-methoxyphenyl H 7-dimethylamino 1101 n-butyl n-butyl OH H

H 7-dimethylamino 1102 n-butyl n-butyl OH H 3-carboxymethylphenyl H 7-dimethylamino 1103 n-butyl n-butyl OH H

H 7-dimethylamino 1104 n-butyl n-butyl OH H

H 7-dimethylamino 1105 n-butyl n-butyl OH H 5-piperonyl H 7-dimethylamino 1106 n-butyl n-butyl OH H 3-hydroxyphenyl H 7-dimethylamino 1107 n-butyl n-butyl OH H

H 7-dimethylamino 1108 n-butyl n-butyl OH H 3-pyridyl H 7-dimethylamino 1109 n-butyl n-butyl OH H

H 7-dimethylamino 1110 n-butyl n-butyl OH H

H 7-dimethylamino 1111 n-butyl n-butyl OH H

H 7-methylamino 1112 n-butyl n-butyl OH H 4-pyridyl H 7-dimethylamino 1113 n-butyl n-butyl OH H

H 7-dimethylamino 1114 n-butyl n-butyl OH H 3-methoxyphenyl H 7-dimethylamino 1115 n-butyl n-butyl OH H 4-fluorophenyl H 7-dimethylamino 1116 ethyl n-butyl OH H 3-tolyl H 7-dimethylamino 1117 ethyl n-butyl OH H

H 7-dimethylamino 1118 ethyl n-butyl OH H 3-fluoro-4-hydroxyphenyl H 7-dimethylamino 1119 n-butyl n-butyl OH H

H 7-dimethylamino 1120 n-butyl n-butyl OH H

H 7-dimethylamino 1121 n-butyl n-butyl OH H

H 7-dimethylamino 1122 n-butyl n-butyl OH H

H 7-dimethylamino 1123 n-butyl n-butyl OH H phenyl H 7-dimethylamino 1124 n-butyl n-butyl OH H 3-methoxyphenyl H 7-dimethylamino 1125 n-butyl n-butyl OH H 3-chloro-4-methoxyphenyl H 7-dimethylamino 1126 ethyl n-butyl OH H

H 7-dimethylamino 1127 n-butyl n-butyl OH H

H 7-dimethylamino 1128 n-butyl n-butyl OH H 3-fluoro-4-hydroxyphenyl H 7-dimethylamino 1129 n-butyl n-butyl OH H 4-fluorophenyl H 9-dimethylamino 1130 n-butyl n-butyl OH H 3-chloro-4-fluorophenyl H 7-dimethylamino 1131 ethyl n-butyl OH H 4-methoxyphenyl H 7-dimethylamino 1132 n-butyl n-butyl OH H

H 7-dimethylamino 1133 n-butyl n-butyl OH H 4-cyanomethylphenyl H 7-dimethylamino 1134 ethyl n-butyl OH H

H 7-dimethylamino 1135 n-butyl n-butyl OH H 3,4-dimethoxyphenyl H 7-dimethylamino 1136 n-butyl n-butyl OH H

H 7-dimethylamino 1137 n-butyl n-butyl OH H 4-fluorophenyl H 9-(2′,2′-dimethylhydrazino) 1138 n-butyl n-butyl OH H

H 7-dimethylamino 1139 n-butyl n-butyl OH H 3,4-difluorophenyl H 7-dimethylamino 1140 n-butyl n-butyl OH H 3-methoxyphenyl H 7-(2′,2′-dimethylhydrazino) 1141 n-butyl n-butyl OH H 4-fluorophenyl H 7-ethylmethylamino 1142 n-butyl n-butyl OH H

H 7-dimethylamino 1143 n-butyl n-butyl H OH H 3-fluoro- 7-dimethylamino 4-methoxy- phenyl 1144 n-butyl n-butyl OH H 5-piperonyl H 7-dimethylamino 1145 n-butyl n-butyl OH H 4-methoxyphenyl H 9-dimethylamino 1146 n-butyl n-butyl OH H

H 7-dimethylamino 1147 n-butyl n-butyl OH H 3-methoxyphenyl H 7-dimethylamino 1148 n-butyl n-butyl OH H 4-fluorophenyl H 7-dimethylsulfonium, fluoride salt 1149 n-butyl n-butyl OH H 4-fluorophenyl H 7-ethylamino 1150 n-butyl n-butyl OH H 3-methoxyphenyl H 7-ethylmethylamino 1151 n-butyl ethyl OH H 3-fluoro-4-methoxyphenyl H 7-dimethylamino 1152 n-butyl n-butyl OH H phenyl H 7-(ethoxymethyl) methylamino 1153 n-butyl n-butyl OH H 4-fluorophenyl H 7-methylamino 1154 n-butyl n-butyl OH H 3-methoxyphenyl H 9-methoxy 1155 n-butyl n-butyl OH H 4-fluorophenyl H 7-methyl 1156 n-butyl n-butyl OH H 4-fluorophenyl H 7-methylmercapto 1157 n-butyl n-butyl OH H 4-fluorophenyl H 7-fluoro; 9-dimethylamino 1158 n-butyl n-butyl OH H 4-pyridinyl, hydrochloride salt H 7-methoxy 1159 n-butyl ethyl OH H phenyl H 7-dimethylamino 1160 n-butyl n-butyl OH H 4-fluorophenyl H 7-dimethylamino 1161 n-butyl n-butyl OH H 3,5-dichloro-4-methoxyphenyl H 7-dimethylamino 1162 n-butyl n-butyl OH H phenyl H 7-dimethylamino 1163 n-butyl n-butyl OH H 3-(dimethylamino)phenyl H 7-methoxy 1164 n-butyl n-butyl OH H 4-pyridinyl H 7-methoxy 1165 n-butyl n-butyl OH H 3-fluoro-4-methoxyphenyl H 7-trimethylammonium iodide 1166 n-butyl n-butyl OH H 3-hydroxyphenyl H 7-trimethylammonium iodide 1167 n-butyl n-butyl OH H

H 7-dimethylamino 1168 n-butyl n-butyl OH H 4-hydroxyphenyl H 7-trimethylammonium iodide 1169 n-butyl n-butyl OH H phenyl H 8-dimethylamino 1170 n-butyl n-butyl OH H 3-methoxyphenyl H 7-ethylpropylamino 1171 n-butyl n-butyl OH H 4-(trifluoromethysulfonyloxy)phenyl H 7-dimethylamino 1172 n-butyl n-butyl OH H 4-pyridinyl H 7-methoxy 1173 n-butyl n-butyl OH H 4-fluorophenyl H 7-ethylpropylamino 1174 ethyl n-butyl OH H 3-methoxyphenyl H 7-phenyl 1175 ethyl n-butyl OH H 3-methoxyphenyl H 7-methylsulfonyl 1176 n-butyl n-butyl OH H 4-fluorophenyl H 9-fluoro 1177 n-butyl n-butyl OH H 3-methoxyphenyl H 7-butylmethylamino 1178 n-butyl n-butyl OH H 3-(trifluoromethylsulfonyloxy)phenyl H 7-dimethylamino 1179 n-butyl n-butyl OH H phenyl H 8-methoxy 1180 n-butyl n-butyl OH H phenyl H 7-trimethylammonium iodide 1181 n-butyl n-butyl OH H 4-fluorophenyl H 7-butylmethylamino 1182 n-butyl n-butyl OH H 4-(dimethylamino)phenyl H 7-methoxy 1183 n-butyl n-butyl OH H 3-methoxyphenyl H 7-fluoro 1184 n-butyl n-butyl OH H 4-fluorophenyl H 7-fluoro; 9-fluoro 1185 n-butyl n-butyl OH H 4-fluorophenyl H 7-fluoro 1186 n-butyl n-butyl OH H phenyl H 7-fluoro; 9-fluoro 1187 n-butyl n-butyl OH H 4-fluorophenyl H 7-methyl 1188 n-butyl n-butyl OH H 4-methoxyphenyl H 7-trimethylammonium iodide 1189 n-butyl n-butyl OH H 3,4-difluorophenyl H 7-trimethylammonium iodide 1190 n-butyl n-butyl OH H 2-bromophenyl H 7-bromo 1191 n-butyl n-butyl OH H 4-(dimethylamino)phenyl H 7-hydroxy 1192 n-butyl n-butyl OH H 3-(dimethylamino)phenyl H 7-hydroxy 1193 n-butyl n-butyl OH H 4-(2-(2-methylpropyl))phenyl H 7-dimethylamino 1194 n-butyl n-butyl OH H

H 7-dimethylamino 1195 n-butyl n-butyl OH H 4-methoxyphenyl H 7-(4′-methylpiperazin-l-yl) 1196 n-butyl n-butyl OH H

H 7-methoxy 1197 n-butyl ethyl R3 + R3 + phenyl H 7-(N-methylformamido) R4 = R4 = oxo oxo 1198 n-butyl n-butyl OH H 4-(pyridinyl-N-oxide) H 7-methoxy 1199 n-butyl n-butyl OH H

H 7-dimethylamino 1200 n-butyl n-butyl H OH H phenyl 7-dimethylamino 1201 n-butyl n-butyl OH H H H 7-methyl 1202 n-butyl n-butyl OH H

H 7-methoxy 1203 n-butyl n-butyl OH H 5-piperazinyl H 7-(4′-tert-butylphenyl) 1204 n-butyl n-butyl OH H 4-fluorophenyl H 7-methoxy 1205 n-butyl n-butyl OH H

H 7-dimethylamino 1206 n-butyl n-butyl OH H

H 7-dimethylamino 1207 n-butyl n-butyl OH H 3,5-dichlorophenyl H 7-dimethylamino 1208 n-butyl n-butyl OH H 4-methoxyphenyl H 7-dimethylamino 1209 n-butyl n-butyl acetox H phenyl H 7-dimethylphenyl y 1210 n-butyl n-butyl OH H 2-(dimethylamino)phenyl H 7-dimethylamino 1211 ethyl n-butyl OH H

H 7-dimethylamino 1212 n-butyl n-butyl OH H 4-methoxyphenyl H 9-(4′-morpholino) 1213 n-butyl ethyl H OH H 3-fluoro- 7-dimethylamino 4-methoxy- phenyl 1214 n-butyl ethyl OH H phenyl H 7-(N-methylformamido) 1215 n-butyl n-butyl OH H 4-methoxyphenyl H 9-methylmercapto 1216 ethyl n-butyl OH H 5-piperonyl H 7-bromo 1217 n-butyl n-butyl OH H 4-carboxyphenyl H 7-dimethylamino 1218 n-butyl n-butyl OH H 4-methoxyphenyl H 9-methylsulfonyl 1219 n-butyl n-butyl OH H

H 7-dimethylamino 1220 n-butyl n-butyl OH H 3-methoxyphenyl H 7-isopropylamino 1221 n-butyl n-butyl OH H

H 7-dimethylamino 1222 n-butyl n-butyl OH H 3-methoxyphenyl H 7-ethylamino 1223 n-butyl n-butyl OH H phenyl H 8-bromo; 7-methylamino 1224 n-butyl n-butyl OH H 3-nitrophenyl H 7-fluoro 1225 n-butyl ethyl OH H 3-methylphenyl H 7-dimethylamino 1226 ethyl n-butyl OH H 5-piperonyl H 7-bromo 1227 n-butyl n-butyl OH H 4-fluorophenyl H 7-(tert-butylamino 1228 n-butyl n-butyl OH H 2-pyrrolyl H 8-bromo; 7-dimethylamino 1229 n-butyl n-butyl OH H 3-chloro-4-hydroxyphenyl H 7-dimethylamino 1230 n-butyl n-butyl OH H phenyl H 9-dimethylamino; 7-fluoro 1231 n-butyl n-butyl OH H

H 7-dimethylamino 1232 n-butyl n-butyl H OH 3-thiophenyl H 9-dimethylamino 1233 n-butyl n-butyl OH H

H 7-dimethylamino 1234 n-butyl n-butyl OH H

H 7-dimethylamino 1235 n-butyl n-butyl OH H

H 7-dimethylamino 1236 n-butyl n-butyl OH H 4-(bromomethyl)phenyl H 7-dimethylamino 1237 n-butyl n-butyl OH H

H 7-dimethylamino 1238 n-butyl n-butyl OH H

H 7-dimethylamino 1239 n-butyl n-butyl OH H

H 7-dimethylamino 1240 n-butyl n-butyl OH H 4-methoxy-3-methylphenyl H 7-dimethylamino 1241 n-butyl n-butyl OH H 3-(dimethylaminomethyl)phenyl H 7-dimethylamino 1242 n-butyl n-butyl OH H

H 7-dimethylamino 1243 n-butyl n-butyl OH H

H 7-dimethylamino 1244 n-butyl n-butyl OH H 3-methoxyphenyl H 7-(1′-methylhydrazido) 1245 n-butyl n-butyl OH H

H 7-dimethylamino 1246 n-butyl n-butyl OH H 3-(bromomethyl)phenyl H 7-dimethylamino 1247 n-butyl n-butyl OH H

H 7-dimethylamino 1248 n-butyl n-butyl OH H

H 7-dimethylamino 1249 n-butyl n-butyl OH H

H 7-dimethylamino 1250 n-butyl n-butyl OH H 3-(dimethylamino)phenyl H 7-dimethylamino 1251 n-butyl n-butyl OH H 1-naphthyl H 7-dimethylamino 1252 n-butyl n-butyl OH H

H 7-dimethylamino 1253 n-butyl n-butyl OH H

H 7-dimethylamino 1254 n-butyl n-butyl OH H

H 7-dimethylamino 1255 n-butyl n-butyl OH H

H 7-dimethylamino 1256 n-butyl n-butyl OH H 3-nitrophenyl H 7-dimethylamino 1257 n-butyl n-butyl OH H phenyl H 8-bromo; 7-dimethylamino 1258 n-butyl n-butyl OH H 4-fluorophenyl H 9-(tert-butylamino) 1259 ethyl n-butyl H OH H phenyl 7-dimethylamino 1260 ethyl n-butyl OH H 3-hydroxyphenyl H 7-dimethylamino 1261 n-butyl n-butyl OH H

H 7-dimethylamino 1262 n-butyl n-butyl OH H 2-thiophenyl H 7-dimethylamino 1263 n-butyl n-butyl OH H 5-piperonyl H 7-bromo 1264 n-butyl n-butyl OH H 4-fluorophenyl H 7-isopropylamino 1265 n-butyl n-butyl OH H 4-fluorophenyl H 9-isopropylamino 1266 n-butyl n-butyl OH H

H 7-dimethylamino 1267 n-butyl ethyl OH H 5-piperonyl H 7-carboxy, methyl ester 1268 n-butyl n-butyl OH H

H 7-dimethylamino 1269 n-butyl n-butyl OH H

H 7-dimethylamino 1270 n-butyl n-butyl OH H

H 7-dimethylamino 1271 n-butyl n-butyl OH H

H 7-dimethylamino 1272 n-butyl n-butyl OH H

H 7-dimethylamino 1273 n-butyl n-butyl OH H

H 7-dimethylamino 1274 n-butyl n-butyl OH H

H 7-dimethylamino 1275 n-butyl n-butyl OH H

H 7-dimethylamino 1276 n-butyl n-butyl OH H

H 7-dimethylamino 1277 n-butyl n-butyl OH H

H 7-dimethylamino 1278 n-butyl n-butyl OH H

H 7-dimethylamino 1279 n-butyl n-butyl OH H

H 7-dimethylamino 1280 n-butyl n-butyl OH H

H 7-dimethylamino 1281 n-butyl n-butyl OH H

H 7-dimethylamino 1282 ethyl n-butyl OH H 3-fluoro-4-methoxyphenyl H 7-trimethylammonium iodide 1283 n-butyl n-butyl OH H 4-hydroxymethylphenyl H 7-dimethylamino 1284 n-butyl n-butyl OH H 4-fluorophenyl H 9-ethylamino 1285 n-butyl ethyl OH H phenyl H 7-dimethylamino 1286 n-butyl n-butyl OH H

H 7-dimethylamino 1287 n-butyl ethyl OH H 4-hydroxyphenyl H 7-dimethylamino 1288 n-butyl n-butyl OH H

H 7-dimethylamino 1289 n-butyl n-butyl OH H

H 7-dimethylamino 1290 n-butyl n-butyl OH H

H 7-dimethylamino 1291 n-butyl n-butyl OH H

H 7-dimethylamino 1292 n-butyl n-butyl OH H

H 7-dimethylamino 1293 n-butyl n-butyl OH H

H 7-dimethylamino 1294 n-butyl n-butyl OH H

H 7-dimethylamino 1295 n-butyl n-butyl OH H

H 7-dimethylamino 1296 n-butyl n-butyl OH H

H 7-dimethylamino 1297 n-butyl n-butyl OH H

H 7-dimethylamino 1298 n-butyl n-butyl OH H

H 7-dimethylamino 1299 n-butyl n-butyl OH H

H 7-dimethylamino 1300 n-butyl ethyl H OH H phenyl 7-dimethylamino 1301 n-butyl n-butyl OH H 3-methoxyphenyl H 7-trimethylammonium iodide 1302 n-butyl n-butyl OH H 4-hydroxyphenyl H 9-hydroxy 1303 n-butyl n-butyl OH H

H 7-dimethylamino 1304 n-butyl n-butyl OH H 3-methoxyphenyl H 7-tert-butylamino 1305 n-butyl n-butyl OH H 4-fluorophenyl H 9-methylamino 1306 n-butyl n-butyl OH H

H 7-dimethylamino 1307 n-butyl n-butyl OH H H 4-methoxy- 9-(4′-morpholino) phenyl 1308 ethyl n-butyl OH H

H 7-dimethylamino 1309 n-butyl n-butyl OH H 4-methoxyphenyl H 9-fluoro 1310 ethyl n-butyl OH H phenyl H 7-amino 1311 n-butyl ethyl OH H phenyl H 7-(hydroxylamino) 1312 n-butyl ethyl OH H phenyl H 8-hexloxy 1313 n-butyl ethyl OH H phenyl H 8-ethoxy 1314 ethyl n-butyl OH H phenyl H 7-(hydroxylamino) 1315 ethyl n-butyl OH H phenyl H 7-(hexyloxy) 1316 n-butyl ethyl OH H phenyl H 8-hydroxy 1317 n-butyl ethyl OH H phenyl H

1318 ethyl n-butyl OH H phenyl H 7-dimethylamino 1319 ethyl n-butyl OH H 3-methoxyphenyl H 7-fluoro 1320 ethyl n-butyl OH H phenyl H 7-amino 1321 n-butyl ethyl OH H phenyl H

1322 n-butyl n-butyl OH H

H 7-dimethylamino 1323 n-butyl n-butyl OH H

H 7-dimethylamino 1324 n-butyl n-butyl OH H

H 7-dimethylamino 1325 n-butyl n-butyl OH H 4-((diethylamino)methyl)phenyl H 7-dimethylamino 1326 n-butyl n-butyl OH H

H 7-dimethylamino 1327 n-butyl n-butyl OH H 3-fluoro-4-hydroxy-5-iodophenyl H 7-dimethylamino 1328 n-butyl n-butyl OH H

H 7-dimethylamino 1329 n-butyl n-butyl OH H

H 7-dimethylamino 1330 n-butyl n-butyl OH H

H 7-dimethylamino 1331 n-butyl n-butyl OH H

H 7-dimethylamino 1332 n-butyl n-butyl OH H

H 7-dimethylamino 1333 n-butyl n-butyl OH H

H 7-dimethylamino 1334 n-butyl n-butyl OH H

H 7-dimethylamino 1335 n-butyl n-butyl OH H

H 7-dimethylamino 1336 n-butyl n-butyl OH H

H 7-dimethylamino 1337 n-butyl n-butyl OH H

H 7-dimethylamino 1338 n-butyl n-butyl OH H 4-methoxyphenyl H 7-(4′-methylpiperazinyl) 1339 n-butyl n-butyl OH H

H 7-dimethylamino 1340 n-butyl ethyl OH H 5-piperonyl H 7-methyl 1341 n-butyl n-butyl acetox H 3-methoxyphenyl H 7-dimethylamino y 1342 n-butyl n-butyl OH H 5-piperonyl H 7-(4′-fluorophenyl) 1343 ethyl n-butyl OH H phenyl H 7-amino 1344 n-butyl n-butyl OH H 3-fluoro-4-methoxyphenyl H 7-dimethylamino 1345 ethyl n-butyl OH H phenyl H 7-trimethylammonium iodide 1346 ethyl n-butyl OH H phenyl H

1347 n-butyl n-butyl OH H 3-fluoro-4-methoxyphenyl H 7-dimethylamino 1348 isobutyl isobutyl OH H phenyl H 7-dimethylamino 1349 ethyl n-butyl OH H phenyl H 7-dimethylamino 1350 n-butyl n-butyl OH H 3-fluoro-4-methoxyphenyl H 7-trimethylammonium iodide 1351 n-butyl n-butyl OH H

H 7-dimethylamino 1352 n-butyl n-butyl OH H

H 7-dimethylamino 1353 n-butyl n-butyl OH H

H 7-dimethylamino 1354 n-butyl n-butyl OH H

H 7-dimethylamino 1355 n-butyl n-butyl OH H

H 7-dimethylamino 1356 n-butyl n-butyl OH H

H 7-dimethylamino 1357 n-butyl n-butyl OH H

H 7-dimethylamino 1358 n-butyl n-butyl OH H

H 7-dimethylamino 1359 n-butyl n-butyl OH H

H 7-dimethylamino 1360 n-butyl n-butyl OH H

H 7-dimethylamino 1361 n-butyl n-butyl OH H

H 7-dimethylamino 1362 n-butyl n-butyl OH H

H 7-dimethylamino 1363 n-butyl n-butyl OH H

H 7-dimethylamino 1364 n-butyl n-butyl OH H

H 7-dimethylamino 1365 n-butyl n-butyl OH H

H 7-dimethylamino 1366 n-butyl n-butyl OH H

H 7-dimethylamino 1367 n-butyl n-butyl OH H

H 7-dimethylamino 1368 n-butyl n-butyl OH H

H 7-dimethylamino 1369 n-butyl n-butyl OH H

H 7-dimethylamino 1370 n-butyl n-butyl OH H

H 7-dimethylamino 1371 n-butyl n-butyl OH H

H 7-dimethylamino 1372 n-butyl n-butyl OH H

H 7-dimethylamino 1373 n-butyl n-butyl OH H

H 7-dimethylamino 1374 n-butyl n-butyl OH H

H 7-dimethylamino 1375 n-butyl n-butyl OH H

H 7-dimethylamino 1376 n-butyl n-butyl OH H

H 7-dimethylamino 1377 n-butyl n-butyl OH H

H 7-dimethylamino 1378 n-butyl n-butyl OH H

H 7-dimethylamino 1379 n-butyl n-butyl OH H

H 7-dimethylamino 1380 n-butyl n-butyl OH H

H 7-dimethylamino 1381 n-butyl n-butyl OH H

H 7-dimethylamino 1382 n-butyl n-butyl OH H

H 7-dimethylamino 1383 n-butyl n-butyl OH H

H 7-dimethylamino 1384 n-butyl n-butyl OH H

H 7-dimethylamino 1385 n-butyl n-butyl OH H

H 7-dimethylamino 1386 n-butyl n-butyl OH H

H 7-dimethylamino 1387 n-butyl n-butyl OH H

H 7-dimethylamino 1388 n-butyl n-butyl OH H

H 7-dimethylamino 1389 n-butyl n-butyl OH H

H 7-dimethylamino 1390 n-butyl n-butyl OH H

H 7-dimethylamino 1391 n-butyl n-butyl OH H

H 7-dimethylamino 1392 n-butyl n-butyl OH H

H 7-dimethylamino 1393 n-butyl n-butyl OH H

H 7-dimethylamino 1394 n-butyl n-butyl OH H

H 7-dimethylamino 1395 n-butyl n-butyl OH H

H 7-dimethylamino 1396 n-butyl n-butyl OH H

H 7-dimethylamino 1397 n-butyl n-butyl OH H

H 7-dimethylamino 1398 n-butyl n-butyl OH H

H 7-dimethylamino 1399 n-butyl n-butyl OH H

H 7-dimethylamino 1400 n-butyl n-butyl OH H

H 7-dimethylamino 1401 n-butyl n-butyl OH H

H 7-dimethylamino 1402 n-butyl n-butyl OH H

H 7-dimethylamino 1403 n-butyl n-butyl OH H

H 7-dimethylamino 1404 n-butyl n-butyl OH H

H 7-dimethylamino 1405 n-butyl n-butyl OH H

H 7-dimethylamino 1406 n-butyl n-butyl OH H

H 7-dimethylamino 1407 n-butyl n-butyl OH H

H 7-dimethylamino 1408 n-butyl n-butyl OH H

H 7-dimethylamino 1409 n-butyl n-butyl OH H

H 7-dimethylamino 1410 n-butyl n-butyl OH H

H 7-dimethylamino 1411 n-butyl n-butyl OH H

H 7-dimethylamino 1412 n-butyl n-butyl OH H

H 7-dimethylamino 1413 n-butyl n-butyl OH H

H 7-dimethylamino 1414 n-butyl n-butyl OH H

H 7-dimethylamino 1415 n-butyl n-butyl OH H

H 7-dimethylamino 1416 n-butyl n-butyl OH H

H 7-dimethylamino 1417 n-butyl n-butyl OH H

H 7-dimethylamino 1418 n-butyl n-butyl OH H

H 7-dimethylamino 1419 n-butyl n-butyl OH H

H 7-dimethylamino 1420 n-butyl n-butyl OH H

H 7-dimethylamino 1421 n-butyl n-butyl OH H

H 7-dimethylamino 1422 n-butyl n-butyl OH H

H 7-dimethylamino 1423 n-butyl n-butyl OH H

H 7-dimethylamino 1424 n-butyl n-butyl OH H

H 7-dimethylamino 1425 n-butyl n-butyl OH H

H 7-dimethylamino 1426 n-butyl n-butyl OH H

H 7-dimethylamino 1427 n-butyl n-butyl OH H

H 7-dimethylamino 1428 n-butyl n-butyl OH H

H 7-dimethylamino 1429 n-butyl n-butyl OH H

H 7-dimethylamino 1430 n-butyl n-butyl OH H

H 7-dimethylamino 1431 n-butyl n-butyl OH H

H 7-dimethylamino 1432 n-butyl n-butyl OH H

H 7-dimethylamino 1433 n-butyl n-butyl OH H

H 7-dimethylamino 1434 n-butyl n-butyl OH H

H 7-dimethylamino 1435 n-butyl n-butyl OH H

H 7-dimethylamino 1436 n-butyl n-butyl OH H

H 7-dimethylamino 1437 n-butyl n-butyl OH H

H 7-dimethylamino 1438 n-butyl n-butyl OH H

H 7-dimethylamino 1439 n-butyl n-butyl OH H

H 7-dimethylamino 1440 n-butyl n-butyl OH H

H 7-dimethylamino 1441 n-butyl n-butyl OH H

H 7-dimethylamino 1442 n-butyl n-butyl OH H

H 7-dimethylamino 1443 n-butyl n-butyl OH H

H 7-dimethylamino 1444 n-butyl n-butyl OH H

H 7-dimethylamino 1445 n-butyl n-butyl OH H

H 7-dimethylamino 1446 n-butyl n-butyl OH H

H 7-methoxy; 8-methoxy 1447 n-butyl n-butyl OH H

H 7-dimethylamino 1448 n-butyl n-butyl OH H

H 7-dimethylamino 1449 n-butyl n-butyl OH H

H 7-dimethylamino 1450 n-butyl n-butyl OH H phenyl H 7-dimethylamino 1451 n-butyl n-butyl OH H

H 7-dimethylamino

Compound Number R⁶ (R^(x))_(q) 101 H

102 H 7-trimethylammonium iodide 103 H 7-trimethylammonium iodide 104 H 7-domethylamino 105 H 7-methanesulfonamido 106 H 7-(2′-bromoacetamido) 107 H 7-amino 108 H 7-(hexylamido) 109 H 7-amino 110 H 7-acetamido 111 H 7-amino 112 H 7-amino 113 H 7-amino 114 H 7-amino 115 H 7-(O-benzylcarbamato) 116 H 7-(O-benzylcarbamato) 117 H 7-(O-benzylcarbamato) 118 H 7-(O-benzylcarbamato) 119 H 7-(O-tert-butylcarbamato) 120 H 7-(O-benzylcarbamato) 121 H 7-amino 122 H 7-amino 123 H 7-hexylamino 124 H 7-(hexylamino) 125 H

126 H 7-(O-benzylcarbamato) 127 H 7-amino 128 H 7-(O-benzylcarbamato) 129 H 7-amino 131 H

132 H

133 H 8-(hexyloxy) 134 H

135 H

136 H 8-hydroxy 137 H

138 H 8-acetoxy 139 H

140 141 142 3-methoxy-phenyl 7-methylmercapto 143 H 7-methylmercapto 144 H 7-(N-azetidinyl) 262 H 7-methoxy 263 3-methoxy-phenyl 7-methoxy 264 H 7-methoxy 265 3-trifluoro-methoxy-phenyl 7-methoxy 266 H 7-hydroxy 267 H 7-methoxy 268 H 7-methoxy 269 4-fluoro-phenyl 7-methoxy 270 H 7-hydroxy 271 H 7-bromo 272 3-methoxy-phenyl 7-bromo 273 4-fluoro-phenyl 7-fluoro 274 H 7-fluoro 275 3-methoxy-phenyl 7-fluoro 276 H 7-fluoro 277 H 7-methoxy 278 H 7-methoxy 279 H 7-methoxy 280 H 7-methoxy 281 H 7-methylmercapto 282 H 7-methyl 283 4-fluoro-phenyl 7-methyl 284 H 7-(4′-morpholino) 286 H 7-(O-benzylcarbamato) 287 H 7-amino 288 H 7-amino 289 H 7-amino 290 H 7-amino 291 H 7-(O-benzylcarbamato) 292 H 7-amino 293 H 7-benzylamino 294 H 7-dimethylamino 295 H 7-amino 296 H 7-amino 1000 H 7-dimethylamino 1001 H 7-dimethylamino 1002 H 7-dimethylamino 1003 H 7-dimethylamino 1004 H 7-dimethylamino 1005 H 7-dimethylamino 1006 H 7-dimethylamino 1007 H 7-dimethylamino 1008 H 7-dimethylamino 1009 H 7-dimethylamino 1010 H 7-dimethylamino 1011 H 7-dimethylamino 1012 H 7-dimethylamino; 9-methoxy 1013 H 7-dimethylamino 1014 H 7-dimethylamino; 9-methoxy 1015 H 7-dimethylamino 1016 H 7-dimethylamino 1017 H 7-dimethylamino 1018 H 7-dimethylamino 1019 H 7-dimethylamino 1020 H 7-dimethylamino 1021 H 7-dimethylamino 1022 H 7-dimethylamino 1023 H 7-dimethylamino 1024 H 7-dimethylamino 1025 H 7-dimethylamino 1026 H 7-dimethylamino 1027 H 7-dimethylamino 1028 H 7-dimethylamino 1029 H 7-dimethylamino 1030 H 7-dimethylamino 1031 H 7-dimethylamino 1032 H 7-dimethylamino 1033 H 7-dimethylamino 1034 H 7-dimethylamino 1035 H 7-dimethylamino 1036 H 7-dimethylamino 1037 H 7-dimethylamino 1038 H 7-dimethylamino 1039 H 7-dimethylamino 1040 H 7-dimethylamino 1041 H 7-dimethylamino 1042 H 7-dimethylamino 1043 H 7-dimethylamino 1044 H 7-dimethylamino 1045 H 7-dimethylamino 1046 H 7-dimethylamino 1047 H 7-dimethylamino 1048 H 7-dimethylamino 1049 H 7-dimethylamino 1050 H 7-dimethylamino 1051 H 7-dimethylamino 1052 H 7-dimethylamino 1053 H 7-dimethylamino 1054 H 7-dimethylamino 1055 H 7-dimethylamino 1056 H 7-dimethylamino 1057 H 7-dimethylamino 1058 H 7-dimethylamino 1059 H 7-dimethylamino 1060 H 7-methylamino 1061 H 7-methylamino 1062 H 7-methylamino 1063 H 7-methylamino 1064 H 7-methylamino 1065 H 7-dimethylamino 1066 H 7-dimethylamino 1067 H 9-dimethylamino 1068 H 7-dimethylamino 1069 H 7-dimethylamino; 9-dimethylamino 1070 H 7-dimethylamino 1071 H 7-dimethylamino 1072 H 7-dimethylamino 1073 H 7-dimethylamino 1074 H 7-dimethylamino 1075 H 7-dimethylamino; 9-dimethylamino 1076 H 7-dimethylamino 1077 H 7-dimethylamino 1078 H 7-dimethylamino 1079 H 7-dimethylamino 1080 H 7-dimethylamino 1081 H 7-dimethylamino 1082 H 7-dimethylamino 1083 H 7-dimethylamino 1084 H 7-dimethylamino 1085 H 7-dimethylamino 1086 H 7-dimethylamino 1087 H 7-dimethylamino 1088 H 7-dimethylamino 1089 H 7-dimethylamino 1090 H 7-dimethylamino 1091 H 7-dimethylamino 1092 H 7-dimethylamino 1093 H 7-dimethylamino 1094 H 7-dimethylamino 1095 H 7-dimethylamino 1096 H 7-dimethylamino 1097 H 7-dimethylamino 1098 H 7-dimethylamino 1099 H 7-dimethylamino 1100 H 7-dimethylamino 1101 H 7-dimethylamino 1102 H 7-dimethylamino 1103 H 7-dimethylamino 1104 H 7-dimethylamino 1105 H 7-dimethylamino 1106 H 7-dimethylamino 1107 H 7-dimethylamino 1108 H 7-dimethylamino 1109 H 7-dimethylamino 1110 H 7-dimethylamino 1111 H 7-dimethylamino 1112 H 7-dimethylamino 1113 H 7-dimethylamino 1114 H 7-methylamino 1115 H 7-dimethylamino 1116 H 7-dimethylamino 1117 H 7-dimethylamino 1118 H 7-dimethylamino 1119 H 7-dimethylamino 1120 H 7-dimethylamino 1121 H 7-dimethylamino 1122 H 7-dimethylamino 1123 H 7-dimethylamino 1124 H 7-dimethylamino 1125 H 7-dimethylamino 1126 H 7-dimethylamino 1127 H 7-dimethylamino 1128 H 7-dimethylamino 1129 H 9-dimethylamino 1130 H 7-dimethylamino 1131 H 7-dimethylamino 1132 H 7-dimethylamino 1133 H 7-dimethylamino 1134 H 7-dimethylamino 1135 H 7-dimethylamino 1136 H 7-dimethylamino 1137 H 9-(2′,2′-dimethylhydrazino) 1138 H 7-dimethylamino 1139 H 7-dimethylamino 1140 H 7-(2′,2′-dimethylhydrazino) 1141 H 7-ethylmethylamino 1142 H 7-dimethylamino 1143 3-fluoro-4-methoxy-phenyl 7-dimethylamino 1144 H 7-dimethylamino 1145 H 9-dimethylamino 1146 H 7-dimethylamino 1147 H 7-diethylamino 1148 H 7-dimethylsulfonium, fluoride salt 1149 H 7-ethylamino 1150 H 7-ethylmethylamino 1151 H 7-dimethylamino 1152 H 7-(ethoxymethyl) methylamino 1153 H 7-methylamino 1154 H 9-methoxy 1155 H 7-methyl 1156 H 7-methylmercapto 1157 H 7-fluoro; 9-dimethylamino 1158 H 7-methoxy 1159 H 7-dimethylamino 1160 H 7-diethylamino 1161 H 7-dimethylamino 1162 H 7-dimethylamino 1163 H 7-methoxy 1164 H 7-methoxy 1165 H 7-trimethylammonium iodide 1166 H 7-trimethylammonium iodide 1167 H 7-dimethylamino 1168 H 7-trimethylammonium iodide 1169 H 8-dimethylamino 1170 H 7-ethylpropylamino 1171 H 7-dimethylamino 1172 H 7-methoxy 1173 H 7-ethylpropylamino 1174 H 7-phenyl 1175 H 7-methylsulfonyl 1176 H 9-fluoro 1177 H 7-butylmethylamino 1178 H 7-dimethylamino 1179 H 8-methoxy 1180 H 7-trimethylammonium iodide 1181 H 7-butylmethylamino 1182 H 7-methoxy 1183 H 7-fluoro 1184 H 7-fluoro; 9-fluoro 1185 H 7-fluoro 1186 H 7-fluoro; 9-fluoro 1187 H 7-methyl 1188 H 7-trimethylammonium iodide 1189 H 7-trimethylammonium iodide 1190 H 7-bromo 1191 H 7-hydroxy 1192 H 7-hydroxy 1193 H 7-dimethylamino 1194 H 7-dimethylamino 1195 H 7-(4′-methylpiperazin-1-yl) 1196 H 7-methoxy 1197 H 7-(N-methylformamido) 1198 H 7-methoxy 1199 H 7-dimethylamino 1200 phenyl 7-dimethylamino 1201 H 7-methyl 1202 H 7-methoxy 1203 H 7-(4′-tert-butylphenyl) 1204 H 7-methoxy 1205 H 7-dimethylamino 1206 H 7-dimethylamino 1207 H 7-dimethylamino 1208 H 7-dimethylamino 1209 H 7-dimethylamino 1210 H 7-dimethylamino 1211 H 7-dimethylamino 1212 H 9-(4′-morpholino) 1213 3-fluoro-4-methoxy-phenyl 7-dimethylamino 1214 H 7-(N-methylformamido) 1215 H 9-methylmercapto 1216 H 7-bromo 1217 H 7-dimethylamino 1218 H 9-methylsulfonyl 1219 H 7-dimethylamino 1220 H 7-isopropylamino 1221 H 7-dimethylamino 1222 H 7-ethylamino 1223 H 8-bromo; 7-methylamino 1224 H 7-fluoro 1225 H 7-dimethylamino 1226 H 7-bromo 1227 H 7-(tert-butylamino 1228 H 8-bromo; 7-dimethylamino 1229 H 7-dimethylamino 1230 H 9-dimethylamino; 7-fluoro 1231 H 7-dimethylamino 1232 H 9-dimethylamino 1233 H 7-dimethylamino 1234 H 7-dimethylamino 1235 H 7-dimethylamino 1236 H 7-dimethylamino 1237 H 7-dimethylamino 1238 H 7-dimethylamino 1239 H 7-dimethylamino 1240 H 7-dimethylamino 1241 H 7-dimethylamino 1242 H 7-dimethylamino 1243 H 7-dimethylamino 1244 H 7-(1′-methylhydrazido) 1245 H 7-dimethylamino 1246 H 7-dimethylamino 1247 H 7-dimethylamino 1248 H 7-dimethylamino 1249 H 7-dimethylamino 1250 H 7-dimethylamino 1251 H 7-dimethylamino 1252 H 7-dimethylamino 1253 H 7-dimethylamino 1254 H 7-dimethylamino 1255 H 7-dimethylamino 1256 H 7-dimethylamino 1257 H 8-bromo; 7-dimethylamino 1258 H 9-(tert-butylamino) 1259 phenyl 7-dimethylamino 1260 H 7-dimethylamino 1261 H 7-dimethylamino 1262 H 7-dimethylamino 1263 H 7-bromo 1264 H 7-isopropylamino 1265 H 9-isopropylamino 1266 H 7-dimethylamino 1267 H 7-carboxy, methyl ester 1268 H 7-dimethylamino 1269 H 7-dimethylamino 1270 H 7-dimethylamino 1271 H 7-dimethylamino 1272 H 7-dimethylamino 1273 H 7-dimethylamino 1274 H 7-dimethylamino 1275 H 7-dimethylamino 1276 H 7-dimethylamino 1277 H 7-dimethylamino 1278 H 7-dimethylamino 1279 H 7-dimethylamino 1280 H 7-dimethylamino 1281 H 7-dimethylamino 1282 H 7-trimethylammonium iodide 1283 H 7-dimethylamino 1284 H 9-ethylamino 1285 H 7-dimethylamino 1286 H 7-dimethylamino 1287 H 7-dimethylamino 1288 H 7-dimethylamino 1289 H 7-dimethylamino 1290 H 7-dimethylamino 1291 H 7-dimethylamino 1292 H 7-dimethylamino 1293 H 7-dimethylamino 1294 H 7-dimethylamino 1295 H 7-dimethylamino 1296 H 7-dimethylamino 1297 H 7-dimethylamino 1298 H 7-dimethylamino 1299 H 7-dimethylamino 1300 phenyl 7-dimethylamino 1301 H 7-trimethylammonium iodide 1302 H 9-hydroxy 1303 H 7-dimethylamino 1304 H 7-tert-butylamino 1305 H 9-methylamino 1306 H 7-dimethylamino 1307 4-methoxy-phenyl 9-(4′-morpholino) 1308 H 7-dimethylamino 1309 H 9-fluoro 1310 H 7-amino 1311 H 7-(hydroxylamino) 1312 H 8-hexyloxy 1313 H 8-ethoxy 1314 H 7-(hydroxylamino) 1315 H 7-(hexyloxy) 1316 H 7-hydroxy 1317 H

1318 H 7-dimethylamino 1319 H 7-fluoro 1320 H 7-amino 1321 H

1322 H 7-dimethylamino 1323 H 7-dimethylamino 1324 H 7-dimethylamino 1325 H 7-dimethylamino 1326 H 7-dimethylamino 1327 H 7-dimethylamino 1328 H 7-dimethylamino 1329 H 7-dimethylamino 1330 H 7-dimethylamino 1331 H 7-dimethylamino 1332 H 7-dimethylamino 1333 H 7-dimethylamino 1334 H 7-dimethylamino 1335 H 7-dimethylamino 1336 H 7-dimethylamino 1337 H 7-dimethylamino 1338 H 7-(4′-methylpiperazinyl) 1339 H 7-dimethylamino 1340 H 7-methylamino 1341 H 7-dimethylamino 1342 H 7-(4′-fluorophenyl) 1343 H 7-amino 1344 H 7-dimethylamino 1345 H 7-trimethylammonium iodide 1346 H

1347 H 7-dimethylamino 1348 H 7-dimethylamino 1349 H 7-dimethylamino 1350 H 7-trimethylammonium iodide 1351 H 7-dimethylamino 1352 H 7-dimethylamino 1353 H 7-dimethylamino 1354 H 7-dimethylamino 1355 H 7-dimethylamino 1356 H 7-dimethylamino 1357 H 7-dimethylamino 1358 H 7-dimethylamino 1359 H 7-dimethylamino 1360 H 7-dimethylamino 1361 H 7-dimethylamino 1362 H 7-dimethylamino 1363 H 7-dimethylamino 1364 H 7-dimethylamino 1365 H 7-dimethylamino 1366 H 7-dimethylamino 1367 H 7-dimethylamino 1368 H 7-dimethylamino 1369 H 7-dimethylamino 1370 H 7-dimethylamino 1371 H 7-dimethylamino 1372 H 7-dimethylamino 1373 H 7-dimethylamino 1374 H 7-dimethylamino 1375 H 7-dimethylamino 1376 H 7-dimethylamino 1377 H 7-dimethylamino 1378 H 7-dimethylamino 1379 H 7-dimethylamino 1380 H 7-dimethylamino 1381 H 7-dimethylamino 1382 H 7-dimethylamino 1383 H 7-dimethylamino 1384 H 7-dimethylamino 1385 H 7-dimethylamino 1386 H 7-dimethylamino 1387 H 7-dimethylamino 1388 H 7-dimethylamino 1389 H 7-dimethylamino 1390 H 7-dimethylamino 1391 H 7-dimethylamino 1392 H 7-dimethylamino 1393 H 7-dimethylamino 1394 H 7-dimethylamino 1395 H 7-dimethylamino 1396 H 7-dimethylamino 1397 H 7-dimethylamino 1398 H 7-dimethylamino 1399 H 7-dimethylamino 1400 H 7-dimethylamino 1401 H 7-dimethylamino 1402 H 7-dimethylamino 1403 H 7-dimethylamino 1404 H 7-dimethylamino 1405 H 7-dimethylamino 1406 H 7-dimethylamino 1407 H 7-dimethylamino 1408 H 7-dimethylamino 1409 H 7-dimethylamino 1410 H 7-dimethylamino 1411 H 7-dimethylamino 1412 H 7-dimethylamino 1413 H 7-dimethylamino 1414 H 7-dimethylamino 1415 H 7-dimethylamino 1416 H 7-dimethylamino 1417 H 7-dimethylamino 1418 H 7-dimethylamino 1419 H 7-dimethylamino 1420 H 7-dimethylamino 1421 H 7-dimethylamino 1422 H 7-dimethylamino 1423 H 7-dimethylamino 1424 H 7-dimethylamino 1425 H 7-dimethylamino 1426 H 7-dimethylamino 1427 H 7-dimethylamino 1428 H 7-dimethylamino 1429 H 7-dimethylamino 1430 H 7-dimethylamino 1431 H 7-dimethylamino 1432 H 7-dimethylamino 1433 H 7-dimethylamino 1434 H 7-dimethylamino 1435 H 7-dimethylamino 1436 H 7-dimethylamino 1437 H 7-dimethylamino 1438 H 7-dimethylamino 1439 H 7-dimethylamino 1440 H 7-dimethylamino 1441 H 7-dimethylamino 1442 H 7-dimethylamino 1443 H 7-dimethylamino 1444 H 7-dimethylamino 1445 H 7-dimethylamino 1446 H 7-methoxy; 8-methoxy 1447 H 7-dimethylamino 1448 H 7-dimethylamino 1449 H 7-dimethylamino 1450 H 7-dimethylamino 1451 H 7-dimethylamino

In further compounds of the present invention, R⁵ and R⁶ are independently selected from among hydrogen and ring-carbon substituted or unsubstituted aryl, thiophene, pyridine, pyrrole, thiazole, imidazole, pyrazole, pyrimidine, morpholine, N-alkylpyridinium, N-alkylpiperazinium, N-alkylmorpholinium, or furan in which the substituent(s) are selected from among halo, hydroxyl, trihaloalkyl, alkoxy, amino, N-alkylamino, N,N-dialkylamino, quaternary ammonium salts, a C₁ to C₄ alkylene bridge having a quaternary ammonium salt substituted thereon, alkoxycarbonyl, aryloxycarbonyl, alkylcarbonyloxy and arylcarbonyloxy, (O,O)-dioxyalkylene,

—[O(CH₂)_(w)]_(x)X where x is 2 to 12, w is 2 or 3 and X comprises halo or a quaternary ammonium salt, thiophene, pyridine, pyrrole, thiazole, imidazole, pyrazole, or furan. The aryl group of R⁵ or R⁶ is preferably phenyl, phenylene, or benzene triyl, i.e., may be unsubstituted, mono-substituted, or di-substituted. Among the species which may constitute the substituents on the aryl ring of R⁵ or R⁶ are fluoro, chloro, bromo, methoxy, ethoxy, isopropoxy, trimethylammonium (preferably with an iodide or chloride counterion), methoxycarbonyl, ethoxycarbonyl, formyl, acetyl, propanoyl, (N)-hexyldimethylammonium, hexylenetrimethylammonium, tri(oxyethylene)iodide, and tetra(oxyethylene)trimethyl-ammonium iodide, each substituted at the p-position, the m-position, or both of the aryl ring. Other substituents that can be present on a phenylene, benzene triyl or other aromatic ring include 3,4-dioxymethylene (5-membered ring) and 3,4-dioxyethylene (6-membered ring). Among compounds which have been or can be demonstrated to have desirable ileal bile acid transport inhibiting properties are those in which R⁵ or R⁶ is selected from phenyl, p-fluorophenyl, m-fluorophenyl, p-hydroxyphenyl, m-hydroxyphenyl, p-methoxyphenyl, m-methoxyphenyl, p-N,N-dimethylaminophenyl, m-N,N-dimethylaminophenyl, I⁻p-(CH₃)₃—N⁺-phenyl, I⁻m-(CH₃)₃—N⁺-phenyl, I⁻m-(CH₃)₃—N⁺—CH₂CH₂—(OCH₂CH₂)₂—O-phenyl, I⁻p-(CH₃)₃—N⁺—CH₂CH₂—(OCH₂CH₂)₂—O-phenyl, I⁻m-(N,N-dimethylpiperazinium) -(N′)—CH₂—(OCH₂CH₂)₂—O-phenyl, 3-methoxy-4-fluorophenyl, thienyl-2-yl, 5-cholorothienyl-2-yl, 3,4-difluorophenyl, I⁻p-(N,N-dimethylpiperazinium)-(N′)—CH₂—(OCH₂CH₂)₂—O-phenyl, 3-fluoro-4-methoxyphenyl, -4-pyridinyl, 2-pyridinyl, 3-pyridinyl, N-methyl-4-pyridinium, I⁻N-methyl-3-pyridinium, 3,4-dioxymethylenephenyl, 3,4-dioxyethylenephenyl, and p-methoxycarbonylphenyl. Preferred compounds include 3-ethyl-3-butyl and 3-butyl-3-butyl compounds having each of the above preferred R⁵ substituents in combination with the R^(x) substituents shown in Table 1. It is particularly preferred that one but not both of R⁵ and R⁶ is hydrogen.

It is especially preferred that R⁴ and R⁶ be hydrogen, that R³ and R⁵ not be hydrogen, and that R³ and R⁵ be oriented in the same direction relative to the plane of the molecule, i.e., both in α- or both in β-configuration. It is further preferred that, where R² is butyl and R¹ is ethyl, then R¹ has the same orientation relative to the plane of the molecule as R³ and R⁵.

Set forth in Table 1A are lists of species of R¹/R², R⁵/R⁶ and R^(x).

TABLE 1A Alternative R Groups

R¹,R² R³,R⁴ R⁵ (R^(x))q ethyl HO— Ph— 7-methyl n-propyl H— p-F-Ph— 7-ethyl n-butyl m-F-Ph— 7-iso-propyl n-pentyl p-CH₃O—Ph— 7-tert-butyl n-hexyl p-CH₃O—Ph— 7-OH iso-propyl m-CH₃O—Ph— 7-OCH₃ iso-butyl p-(CH₃)₂N—Ph— 7-O(iso-propyl) iso-pentyl m-(CH₃)₂N—Ph— 7-SCH₃ CH₂C(═O)C₂H₅ I⁻, p-(CH₃)₃—N⁺—Ph— 7-SOCH₃ CH₂OC₂H₅ I⁻, m-(CH₃)₃—N⁺—Ph— 7-SO₂CH₃ CH₂CH(OH)C₂H₅ I⁻, p-(CH₃)₃—N⁺—Ph— 7-SCH₂CH₃ CH₂O-(4-picoline) (OCH₂CH₂)—O—Ph— 7-NH₂ I⁻, m-(CH₃)₃—N⁺—CH₂CH₂— 7-NHOH (OCH₂CH₂)₂—O—Ph— 7-NHCH₃ I⁻, p-(N,N- 7-N(CH₃)₂ dimethylpiperazine)- 7-N⁺(CH₃)₃, I⁻ (N′)—CH₂—(OCH₂CH₂)₂—O—Ph— 7-NHC(═O)CH₃ I⁻, m-(N,N- 7-N(CH₂CH₃)₂ dimethylpiperazine)- 7-NMeCH₂CO₂H (N′)-CH₂—(OCH₂CH₂)₂—O—Ph— 7-N⁺(Me)₂CH₂CO₂H, I⁻ m-F, p-CH₃O—Ph— 7-(N)-morpholine 3,4,dioxymethylene-Ph 7-(N)-azetidine m-CH₃O—, p-F—Ph— 7-(N)-N-methylazetidinium, I⁻ 4-pyridine 7-(N)-pyrrolidine N-methyl-4-pyridinium, I⁻ 7-(N)-N-methyl- 3-pyridine pyrrolidinium, I⁻ N-methyl-3-pyridinium, I⁻ 7-(N)-N-methyl- 2-pyridine morpholinium, I⁻ p-CH₃O₂C—Ph— 7-(N)-N′-methylpiperazine thienyl-2-yl 7-(N)-N′-dimethylpiperazinium, I⁻ 5-Cl-thienyl-2-yl 7-NH-CBZ 7-NHC(O)C₅H₁₁ 7-NHC(O)CH₂Br 7-NH—C(NH)NH₂ 7-(2)-thiophene 8-methyl 8-ethyl 8-iso-propyl 8-tert-butyl 8-OH 8-OCH₃ 8-O(iso-propyl) 8-SCH₃ 8-SOCH₃ 8-SO₂CH₃ 8-SCH₂CH₃ 8-NH₂ 8-NHOH 8-NHCH₃ 8-N(CH₃)₂ 8-N⁺(CH₃)₃, I⁻ 8-NHC(═O)CH₃ 8-N(CH₂CH₃) ₂ 8-NMeCH₂CO₂H 8-N⁺(Me)₂CH₂CO₂H, I⁻ 8-(N)-morpholine 8-(N)-azetidine 8-(N)-N-methylazetidinium, I⁻ 8-(N)-pyrrolidine 8-(N)-N-methylpyrrolidinium, I⁻ 8-(N)-N-methylmorpholinium, I⁻ 8-(N)-N′-methylpiperazine 8-(N)-N′-dimethylpiperazinium, I⁻ 8-NH-CBZ 8-NHC(O)C₅H₁₁ 8-NHC(O)CH₂Br 8-NH-C(NH)NH₂ 8-(2)-thiophene 9-methyl 9-ethyl 9-iso-propyl 9-tert-butyl 9-OH 9-OCH₃ 9-O(iso-propyl) 9-SCH₃ 9-SOCH₃ 9-SO₂CH₃ 9-SCH₂CH₃ 9-NH₂ 9-NHOH 9-NHCH₃ 9-N(CH₃)₂ 9-N⁺(CH₃)₃, I⁻ 9-NHC(═O)CH₃ 9-N(CH₂CH₃)₂ 9-NMeCH₂CO₂H 9-N⁺(Me)₂CH₂CO₂H, I⁻ 9-(N)-morpholine 9-(N)-azetidine 9-(N)-N-methylazetidinium, I⁻ 9-(N)-pyrrolidine 9-(N)-N-methylpyrrolidlne, I⁻ 9-(N)-N-methylmorpholinium, I⁻ 9-(N)-N′-methylpiperazine 9-(N)-N′-dimethylpiperazinium, I⁻ 9-NH-CBZ 9-NHC(O)C₅H₁₁ 9-NHC(O)CH₂Br 9-NH—C(NH)NH₂ 9-(2)-thiophene 7-OCH₃, 8-OCH₃ 7-SCH₃, 8-OCH₃ 7-SCH₃, 8-SCH₃ 6-OCH₃, 7-OCH₃, 8-OCH₃

Further preferred compounds of the present invention comprise a core structure having two or more pharmaceutically active benzothiepine structures as described above, covalently bonded to the core moiety via functional linkages. Such active benzothiepine structures preferably comprise:

where R¹, R², R³, R⁴, R⁶, R⁵, R⁶, R⁷, R⁸, X, q and n are as defined above, and R⁵⁵ is either a covalent bond or arylene.

The core moiety can comprise alkane diyl, alkene diyl, alkyne diyl, polyalkane diyl, alkoxy diyl, polyether diyl, polyalkoxy diyl, carbohydrate, amino acid, and peptide, polypeptide, wherein alkane diyl, alkene diyl, alkyne diyl, polyalkane diyl, alkoxy diyl, polyether diyl, polyalkoxy diyl, carbohydrate, amino acid, and peptide polypeptide, can optionally have one or more carbon replaced by O, NR⁷, N⁺R⁷R⁸, S, SO, SO2, S⁺R⁷R⁸, PR7, P+R7R8, phenylene, heterocycle, quatarnary heterocycle, quaternary heteroaryl, or aryl,

wherein alkane diyl, alkene diyl, alkyne diyl, polyalkane diyl, alkoxy diyl, polyether diyl, polyalkoxy diyl, carbohydrate, amino acid, peptide, and polypeptide can be substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR¹³, NR¹³R¹⁴, SR¹³, S(O)R¹³, SO₂R¹³, SO₃R¹³, NR¹³OR¹⁴, NR¹³NR¹⁴R¹⁵, NO₂, CO₂R¹³, CN, OM, SO₂OM, SO₂NR¹³R¹⁴, C(O)NR¹³R¹⁴, C(O)OM, COR¹³, P(O)R¹³R¹⁴, P⁺R¹³R¹⁴R15A—, P(OR¹³)OR¹⁴, S⁺R¹³R¹⁴A⁻, and N⁺R⁹R¹¹R¹²A⁻;

wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can be further substituted with one or more substituent groups selected from the group consisting of OR⁷, NR⁷R⁸, SR⁷, S(O)R⁷, SO₂R⁷, SO₃R⁷, CO₂R⁷, CN, oxo, CONR⁷R⁸, N⁺R⁷R⁸R⁹A—, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, P(O)R⁷R⁸, P⁺R⁷R⁸A⁻, and P(O)(OR⁷)OR⁸, and

wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can optionally have one or more carbons replaced by O, NR⁷, N⁺R⁷R⁸A—, S, SO, SO₂, S⁺R⁷A—, PR⁷, P(O)R⁷, P⁺R⁷R⁸A—, or phenylene.

Exemplary core moieties include:

wherein:

R²⁵ is selected from the group consisting of C and N, and

R²⁶ and R²⁷ are independently selected from the group consisting of:

wherein R²⁶, R²⁹, R³⁰ and R³¹ are independently selected from alkyl, alkenyl, alkylaryl, aryl, arylalkyl, cycloalkyl, heterocycle, and heterocycloalkyl,

A⁻ is a pharmaceutically acceptable anion, and k=1 to 10.

In compounds of Formula DIV, R²⁰, R²¹, R²² in Formulae DII and DIII, and R²³ in Formula DIII can be bonded at any of their 6-, 7-, 8-, or 9-positions to R¹⁹. In compounds of Formula DIVA, it is preferred that R⁵⁵ comprises a phenylene moiety bonded at a m- or p-position thereof to R¹⁹.

In another embodiment, a core moiety backbone, R¹⁹, as discussed herein in Formulas DII and DIII can be multiply substituted with more than four pendant active benzothiepine units, i.e., R²⁰, R²¹, R²², and R²³ as discussed above, through multiple functional groups within the core moiety backbone. The core moiety backbone unit, R¹⁹, can comprise a single core moiety unit, multimers thereof, and multimeric mixtures of the different core moiety units discussed herein, i.e., alone or in combination. The number of individual core moiety backbone units can range from about one to about 100, preferably about one to about 80, more preferably about one to about 50, and even more preferably about one to about 25. The number of points of attachment of similar or different pendant active benzothiepine units within a single core moiety backbone unit can be in the range from about one to about 100, preferably about one to about 80, more preferably about one to about 50, and even more preferably about one to about 25. Such points of attachment can include bonds to C, S, O, N, or P within any of the groups encompassed by the definition of R¹⁹.

The more preferred benzothiepine moieties comprising R²⁰, R²¹, R²² and/or R²³ conform to the preferred structures as outlined above for Formula I. The 3-carbon on each benzothiepine moiety can be achiral, and the substituents R¹, R², R³, R⁴, R⁵ and R^(x) can be selected from the preferred groups and combinations of substituents as discussed above. The core structures can comprise, for example, poly(exyalkylene) or oligo(oxyalkylene), especially poly- or oligo(exyethylene) or poly- or oligo(oxypropylene).

Dosages, Formulations, and Routes of Administration

The ileal bile acid transport inhibitor compounds of the present invention can be administered for the prophylaxis and treatment of hyperlipidemic diseases or conditions by any means, preferably oral, that produce contact of these compounds with their site of action in the body, for example in the ileum of a mammal, e.g., a human.

For the prophylaxis or treatment of the conditions referred to above, the compounds of the present invention can be used as the compound per se.

Pharmaceutically acceptable salts are particularly suitable for medical applications because of their greater aqueous solubility relative to the parent compound. Such salts must clearly have a pharmaceutically acceptable anion or cation. Suitable pharmaceutically acceptable acid addition salts of the compounds of the present invention when possible include those derived from inorganic acids, such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric, sulfonic, and sulfuric acids, and organic acids such as acetic, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isothionic, lactic, lactobionic, maleic, malic, methanesulfonic, succinic, toluenesulfonic, tartaric, and trifluoroacetic acids. The chloride salt is particularly preferred for medical purposes. Suitable pharmaceutically acceptable base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, and alkaline earth salts such as magnesium and calcium salts.

The anions of the definition of A⁻ in the present invention are, of course, also required to be pharmaceutically acceptable and are also selected from the above list.

The compounds of the present invention can be presented with an acceptable carrier in the form of a pharmaceutical composition. The carrier must, of course, be acceptable in the sense of being compatible with the other ingredients of the composition and must not be deleterious to the recipient. The carrier can be a solid or a liquid, or both, and is preferably formulated with the compound as a unit-dose composition, for example, a tablet, which can contain from 0.05% to 95% by weight of the active compound. Other pharmacologically active substances can also be present, including other compounds of the present invention. The pharmaceutical compositions of the invention can be prepared by any of the well known techniques of pharmacy, consisting essentially of admixing the components.

These compounds can be administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic compounds or as a combination of therapeutic compounds.

The amount of compound which is required to achieve the desired biological effect will, of course, depend on a number of factors such as the specific compound chosen, the use for which it is intended, the mode of administration, and the clinical condition of the recipient.

In general, a daily dose can be in the range of from about 0.3 to about 100 mg/kg bodyweight/day, preferably from about 1 mg to about 50 mg/kg bodyweight/day, more preferably from about 3 to about 10 mg/kg bodyweight/day. This total daily dose can be administered to the patient in a single dose, or in proportionate multiple subdoses. Subdoses can be administered 2 to 6 times per day. Doses can be in sustained release form effective to obtain desired results.

Orally administrable unit dose formulations, such as tablets or capsules, can contain, for example, from about 0.1 to about 100 mg of benzothiepine compound, preferably about 1 to about 75 mg of compound, more preferably from about 10 to about 50 mg of compound. In the case of pharmaceutically acceptable salts, the weights indicated above refer to the weight of the benzothiepine ion derived from the salt.

Oral delivery of an ileal bile acid transport inhibitor of the present invention can include formulations, as are well known in the art, to provide prolonged or sustained delivery of the drug to the gastrointestinal tract by any number of mechanisms. These include, but are not limited to, pH sensitive release from the dosage form based on the changing pH of the small intestine, slow erosion of a tablet or capsule, retention in the stomach based on the physical properties of the formulation, bioadhesion of the dosage form to the mucosal lining of the intestinal tract, or enzymatic release of the active drug from the dosage form. The intended effect is to extend the time period over which the active drug molecule is delivered to the site of action (the ileum) by manipulation of the dosage form. Thus, enteric-coated and enteric-coated controlled release formulations are within the scope of the present invention. Suitable enteric coatings include cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropylmethylcellulose phthalate and anionic polymers of methacrylic acid and methacrylic acid methyl ester.

When administered intravenously, the dose can, for example, be in the range of from about 0.1 mg/kg body weight to about 1.0 mg/kg body weight, preferably from about 0.25 mg/kg body weight to about 0.75 mg/kg body weight, more preferably from about 0.4 mg/kg body weight to about 0.6 mg/kg body weight. This dose can be conveniently administered as an infusion of from about 10 ng/kg body weight to about 100 ng/kg body weight per minute. Infusion fluids suitable for this purpose can contain, for example, from about 0.1 ng to about 10 mg, preferably from about 1 ng to about 10 mg per milliliter. Unit doses can contain, for example, from about 1 mg to about 10 g of the compound of the present invention. Thus, ampoules for injection can contain, for example, from about 1 mg to about 100 mg.

Pharmaceutical compositions according to the present invention include those suitable for oral, rectal, topical, buccal (e.g., sublingual), and parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous) administration, although the most suitable route in any given case will depend on the nature and severity of the condition being treated and on the nature of the particular compound which is being used. In most cases, the preferred route of administration is oral.

Pharmaceutical compositions suitable for oral administration can be presented in discrete units, such as capsules, cachets, lozenges, or tablets, each containing a predetermined amount of at least one compound of the present invention; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion. As indicated, such compositions can be prepared by any suitable method of pharmacy which includes the step of bringing into association the active compound(s) and the carrier (which can constitute one or more accessory ingredients). In general, the compositions are prepared by uniformly and intimately admixing the active compound with a liquid or finely divided solid carrier, or both, and then, if necessary, shaping the product. For example, a tablet can be prepared by compressing or molding a powder or granules of the compound, optionally with one or more assessory ingredients. Compressed tablets can be prepared by compressing, in a suitable machine, the compound in a free-flowing form, such as a powder or granules optionally mixed with a binder, lubricant, inert diluent and/or surface active/dispersing agent(s). Molded tablets can be made by molding, in a suitable machine, the powdered compound moistened with an inert liquid diluent.

Pharmaceutical compositions suitable for buccal (sub-lingual) administration include lozenges comprising a compound of the present invention in a flavored base, usually sucrose, and acacia or tragacanth, and pastilles comprising the compound in an inert base such as gelatin and glycerin or sucrose and acacia.

Pharmaceutical compositions suitable for parenteral administration conveniently comprise sterile aqueous preparations of a compound of the present invention. These preparations are preferably administered intravenously, although administration can also be effected by means of subcutaneous, intramuscular, or intradermal injection. Such preparations can conveniently be prepared by admixing the compound with water and rendering the resulting solution sterile and isotonic with the blood. Injectable compositions according to the invention will generally contain from 0.1 to 5% w/w of a compound disclosed herein.

Pharmaceutical compositions suitable for rectal administration are preferably presented as unit-dose suppositories. These can be prepared by admixing a compound of the present invention with one or more conventional solid carriers, for example, cocoa butter, and then shaping the resulting mixture.

Pharmaceutical compositions suitable for topical application to the skin preferably take the form of an ointment, cream, lotion, paste, gel, spray, aerosol, or oil. Carriers which can be used include vaseline, lanoline, polyethylene glycols, alcohols, and combinations of two or more thereof. The active compound is generally present at a concentration of from 0.1 to 15% w/w of the composition, for example, from 0.5 to 2%.

Transdermal administration is also possible. Pharmaceutical compositions suitable for transdermal administration can be presented as discrete patches adapted to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. Such patches suitably contain a compound of the present invention in an optionally buffered, aqueous solution, dissolved and/or dispersed in an adhesive, or dispersed in a polymer. A suitable concentration of the active compound is about 1% to 35%, preferably about 3% to 15%. As one particular possibility, the compound can be delivered from the patch by electrotransport or iontophoresis, for example, as described in Pharmaceutical Research, 3(6), 318 (1986).

In any case, the amount of active ingredient that can be combined with carrier materials to produce a single dosage form to be administered will vary depending upon the host treated and the particular mode of administration.

The solid dosage forms for oral administration including capsules, tablets, pills, powders, and granules noted above comprise one or more compounds of the present invention admixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms may also comprise, as in normal practice, additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.

Liquid dosage forms for oral administration can include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Such compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.

Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or setting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

Pharmaceutically acceptable carriers encompass all the foregoing and the like.

Treatment Regimen

The dosage regimen to prevent, give relief from, or ameliorate a disease condition having hyperlipemia as an element of the disease, e.g., atherosclerosis, or to protect against or treat further high cholesterol plasma or blood levels with the compounds and/or compositions of the present invention is selected in accordance with a variety of factors. These include the type, age, weight, sex, diet, and medical condition of the patient, the severity of the disease, the route of administration, pharmacological considerations such as the activity, efficacy, pharmacokinetics and toxicology profiles of the particular compound employed, whether a drug delivery system is utilized, and whether the compound is administered as part of a drug combination. Thus, the dosage regimen actually employed may vary widely and therefore deviate from the preferred dosage regimen set forth above.

Initial treatment of a patient suffering from a hyperlipidemic condition can begin with the dosages indicated above. Treatment should generally be continued as necessary over a period of several weeks to several months or years until the hyperlipidemic disease condition has been controlled or eliminated. Patients undergoing treatment with the compounds or compositions disclosed herein can be routinely monitored by, for example, measuring serum cholesterol levels by any of the methods well known in the art, to determine the effectiveness of therapy. Continuous analysis of such data permits modification of the treatment regimen during therapy so that optimal effective amounts of compounds of the present invention are administered at any point in time, and so that the duration of treatment can be determined as well. In this way, the treatment regimen/dosing schedule can be rationally modified over the course of therapy so that the lowest amount of ileal bile acid transport inhibitor of the present invention which exhibits satisfactory effectiveness is administered, and so that administration is continued only so long as is necessary to successfully treat the hyperlipidemic condition.

The following non-limiting examples serve to illustrate various aspects of the present invention.

EXAMPLES OF SYNTHETIC PROCEDURES

Preparation 1

2-Ethyl-2-(mesyloxymethyl)hexanal (1)

To a cold (10° C.) solution of 12.6 g (0.11 mole) of methanesulfonyl chloride and 10.3 g (0.13 mole) of triethylamine was added dropwise 15.8 g of 2-ethyl-2-(hydroxymethyl)hexanal, prepared according to the procedure described in Chem. Ber. 98, 728-734 (1965), while maintaining the reaction temperature below 30° C. The reaction mixture was stirred at room temperature for 18 h, quenched with dilute HCl and extracted with methlyene chloride. The methylene chloride extract was dried over MgSO₄ and concentrated in vacuo to give 24.4 g of brown oil.

Preparation 2

2-((2-Benzoylphenylthio)methyl)-2-ethylhexanal (2)

A mixture of 31 g (0.144 mol) of 2-mercaptobenzophenone, prepared according to the procedure described in WO 93/16055, 24.4 g (0.1 mole) of 2-ethyl-2-(mesyloxymethyl)-hexanal (1), 14.8 g (0.146 mole) of triethylamine, and 80 mL of 2-methoxyethyl ether was held at reflux for 24 h. The reaction mixture was poured into 3N HCl and extracted with 300 mL of methylene chloride. The methylene chloride layer was washed with 300 mL of 10% NaOH, dried over MgSO₄ and concentrated in vacuo to remove 2-methoxyethyl ether. The residue was purified by HPLC (10% EtOAc-hexane) to give 20.5 g (58%) of 2 as an oil.

Example 1 3-Butyl-3-ethyl-5-phenyl-2,3-dihydrobenzothiepine (3), cis-3-Butyl-3-ethyl-5-phenyl-2,3-dihydrobenzothiepin-(5H)4-one (4a) and trans-3-Butyl-3-ethyl-5-phenyl-2,3-dihydro-benzothiepin-(5H)4-one (4b)

A mixture of 2.6 g (0.04 mole) of zinc dust, 7.2 g (0.047 mole) of TiCl₃ and 80 mL of anhydrous ethylene glycol dimethyl ether (DME) was held at reflux for 2 h. The reaction mixture was cooled to 5° C. To the reaction mixture was added dropwise a solution of 3.54 g (0.01 mole) of 2 in 30 mL of DME in 40 min. The reaction mixture was stirred at room temperature for 16 h and then was held at reflux for 2 h and cooled before being poured into brine. The organic was extract into methylene chloride. The methylene chloride extract was dried over MgSO₄ and concentrated in vacuo. The residue was purified by HPLC (hexane) to give 1.7 g (43%) of 3 as an oil in the first fraction. The second fraction was discarded and the third fraction was further purified by HPLC (hexane) to give 0.07 g (2%) of 4a in the earlier fraction and 0.1 g (3%) of 4b in the later fraction.

Example 2 cis-3-Butyl-3-ethyl-5-phenyl-2,3-dihydrobenzothiepin-(5H) 4-one-1,1-dioxide (5a) and trans-3-Butyl-3-ethyl-5-phenyl-2,3-dihydro-benzothiepin-(5H) 4-one-1,1-dioxide (5b)

To a solution of 1.2 g (3.5 mmole) of 50-60% MCPBA in 20 mL of methylene chloride was added 0.59 g (1.75 mmole) of a mixture of 4a and 4b in 10 mL of methylene chloride. The reaction mixture was stirred for 20 h. An additional 1.2 g (1.75 mmole) of 50-60% MAPBA was added and the reaction mixture was stirred for an additional 3 h then was triturated with 50 mL of 10% NaOH. The insoluble solid was filtered. The methylene chloride layer of the filtrate was washed with brine, dried over MgSO₄, and concentrated in vacuo. The residual syrup was purified by HPLC (5% EtOAc-hexane) to give 0.2 g (30%) of 5a as an oil in the first fraction and 0.17 g (26%) of 5b as an oil in the second fraction.

Example 3 (3α,4α,5β) 3-Butyl-3-ethyl-4-hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (6a), (3α,4β,5α) 3-Butyl-3-ethyl-4-hydroxy-5-phenyl-2,3,4,5-tetrahydro-benzothiepine-1,1-dioxide (6b), (3α,4α,5α) 3-Butyl-3-ethyl-4-hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (6c), and (3α,4β,5β) 3-Butyl-3-ethyl-4-hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (6d)

A. Reduction of 5a and 5b with Sodium Borohydride

To a solution of 0.22 g (0.59 mmole) of 5b in 10 mL of ethanol was added 0.24 g (6.4 mmole) of sodium borohydride. The reaction mixture was stirred at room temperature for 18 h and concentrated in vacuo to remove ethanol. The residue was triturated with water and extracted with methylene chloride. The methylene chloride extract was dried over MgSO₄ and concentrated in vacuo to give 0.2 g of syrup. In a separate experiment, 0.45 g of 5a was treated with 0.44 g of sodium borohydride in 10 mL of ethanol and was worked up as described above to give 0.5 g of syrup which was identical to the 0.2 g of syrup obtained above. These two materials were combined and purified by HPLC using 10% EtOAc-hexane as eluant. The first fraction was 0.18 g (27%) of 6a as a syrup. The second fraction was 0.2 g (30%) of 6b also as a syrup. The column was then eluted with 20% EtOAc-hexane to give 0.077 g (11%) of 6c in the third fraction as a solid. Recrystallization from hexane gave a solid, mp 179-181° C. Finally, the column was eluted with 30% EtOAc-hexane to give 0.08 g (12%) of 6d in the fourth fraction as a solid. Recrystallization from hexane gave a solid, mp 160-161° C.

B. Conversion of 6a to 6c and 6d with NaOH and PTC

To a solution of 0.29 g (0.78 mmole) of 6a in 10 mL CH₂Cl₂, was added 9 g of 40% NaOH. The reaction mixture was stirred for 0.5 h at room temperature and was added one drop of Aliquat-336 (methyltricaprylylammonium chloride) phase transfer catalyst (PTC). The mixture was stirred for 0.5 h at room temperature before being treated with 25 mL of ice-crystals then was extracted with CH₂Cl₂ (3×10 ml), dried over MgSO₄ and concentrated in vacuo to recover 0.17 g of a colorless film. The components of this mixture were separated using an HPLC and eluted with EtOAc-hexane to give 12.8 mg (4%) of 2-(2-benzylphenylsulfonylmethyl)-2-ethylhexenal in the first fraction, 30.9 mg (11%) of 6c in the second fraction and 90.0 mg (31%) of 6d in the third fraction.

Oxidation of 6a to 5b

To a solution of 0.20 g (0.52 mmole) of 6a in 5 mL of CH₂Cl₂ was added 0.23 g (1.0 mmole) of pyridinium chlorochromate. The reaction mixture was stirred for 2 h then was treated with additional 0.23 g of pyridinium chlorochromate and stirred overnight. The dark reaction mixture was poured into a ceramic filterfrit containing silica gel and was eluted with CH₂Cl₂. The filtrate was concentrated in vacuo to recover 167 mg (87%) of 5b as a colorless oil.

Example 4 3-Butyl-3-ethyl-5-phenyl-2,3-dihydrobenzothiepine-1,1-dioxide (7)

To a solution of 5.13 g (15.9 mmole) of 3 in 50 mL of CH₂Cl₂ was added 10 g (31.9 mmole)of 50-60% MCPBA (m-chloroperoxybenzoic acid) portionwise causing a mild reflux and formation of a white solid. The reaction mixture was allowed to stir overnight under N₂ and was triturated with 25 mL of water followed by 50 mL of 10% NaOH solution. The organic was extracted into CH₂Cl₂ (4×20 mL). The CH₂Cl₂ extract was dried over MgSO₄ and evaporated to dryness to recover 4.9 g (87%) of an opaque viscous oil.

Example 5 (1aα,2β,8bα) 2-Butyl-2-ethyl-8b-phenyl-1α,2,3,8b-tetrahydro-benzothiepino[4,5-b]oxirene-4,4-dioxide (8a) (1aα,2α,8bα) 2-Butyl-2-ethyl-8b-phenyl-1a,2,3,8b-tetrahydro-benzothiepino[4,5-b]oxirene-4,4-dioxide (8b)

To 1.3 g (4.03 mole) of 3 in 25 mL of CHCl₃ was added portionwise 5 g (14.1 mmole) of 50-60% MCPBA causing a mild exotherm. The reaction mixture was stirred under N₂ overnight and was then held at reflux for 3 h. The insoluble white slurry was filtered. The filtrate was extracted with 10% potassium carbonate (3×50 mL), once with brine, dried over MgSO₄, and concentrated in vacuo to give 1.37 g of a light yellow oil. Purification by HPLC gave 0.65 g of crystalline product. This product is a mixture of two isomers. Trituration of this crystalline product in hexane recovered 141.7 mg (10%) of a white crystalline product. This isomer was characterized by NMR and mass spectra to be the (1aα,2β,8bα) isomer 8a. The hexane filtrate was concentrated in vacuo to give 206 mg of white film which is a mixture of 30% 8a and 70% 8b by ¹H NMR.

Example 6 cis-3-Butyl-3-ethyl-5-phenyl-2,3,4,5-tetrahydro-benzothiepine-1,1-dioxide (9a), trans-3-Butyl-3-ethyl-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (9b), and 3-Butyl-3-ethyl-4-hydroxy-5-cyclohexylidine-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (10)

A mixture of 0.15 g (0.4 mmole) of a 3:7 mixture of 8a and 8b was dissolved in 15 ml MeOH in a 3 oz. Fisher/Porter vessel, then was added 0.1 g of 10% Pd/C catalyst. This mixture was hydrogenated at 70 psi H₂ for 5 h and filtered. The filtrate was evaporated to dryness in vacuo to recover 0.117 g of a colorless oil. This material was purified by HPLC eluting with EtOAc-hexane. The first fraction was 4.2 mg (3%) of 9b. The second fraction, 5.0 mg (4%), was a 50/50 mixture of 9a and 9b. The third fraction was 8.8 mg (6%) of 6a. The fourth fraction was 25.5 mg (18%) of 6b. The fifth fraction was 9.6 mg (7%) of a mixture of 6b and a product believed to be 3-butyl-3-ethyl-4,5-dihydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide based on mass spectrum. The sixth fraction was 7.5 mg (5%) of a mixture of 6d and one of the isomers of 10, 10a.

Example 7

In another experiment, a product (3.7 g) from epoxidation of 3 with excess MCPBA in refluxing CHCl₃ under air was hydrogenated in 100 mL of methanol using 1 g of 10% Pd/C catalyst and 70 psi hydrogen. The product was purified by HPLC to give 0.9 g (25%) of 9b, 0.45 g (13%) of 9a, 0.27 g (7%) of 6a, 0.51 g (14%) of 6b, 0.02 g (1%) of 6c, 0.06 g (2%) of one isomer of 10, 10a and 0.03 g (1%) of another isomer of 10, 10b.

Example 8 2-((2-Benzoylphenylthio)methyl)butyraldehyde (11)

To an ice bath cooled solution of 9.76 g (0.116 mole) of 2-ethylacrolein in 40 mL of dry THF was added 24.6 g (0.116 mole) of 2-mercaptobenzophenone in 40 mL of THF followed by 13 g (0.128 mole) of triethylamine. The reaction mixture was stirred at room temperature for 3 days, diluted with ether, and was washed successively with dilute HCl, brine, and 1 M potassium carbonate. The ether layer was dried over MgSO₄ and concentrated in vacuo. The residue was purified by HPLC (10% EtOAc-hexane) to give 22 g (64%) of 11 in the second fraction. An attempt to further purifiy this material by kugelrohr distillation at 0.5 torr (160-190° C.) gave a fraction (12.2 g) which contained starting material indicating a reversed reaction during distillation. This material was dissolved in ether (100 mL) and was washed with 50 mL of 1 M potassium carbonate three times to give 6.0 g of a syrup which was purified by HPLC (10% EtOAc-hexane) to give 5.6 g of pure 11.

Example 9 3-Ethyl-5-phenyl-2,3-dihydrobenzothiepine (12)

To a mixture of 2.61 g (0.04 mole) of zinc dust and 60 mL of DME was added 7.5 g (0.048 mole) of Ticl₃. The reaction mixture was held at reflux for 2 h. A solution of 2.98 g (0.01 mole) of 11 was added dropwise in 1 h. The reaction mixture was held at reflux for 18 h, cooled and poured into water. The organic was extracted into ether. The ether layer was washed with brine and filtered through Celite. The filtrate was dried over MgSO₄ and concentrated. The residual oil (2.5 g) was purified by HPLC to give 2.06 g (77%) of 12 as an oil in the second fraction.

Example 10 (1aα,2α,8bα) 2-Ethyl-8b-phenyl-1a,2,3,8b-tetrahydro-benzothiepino-[4,5-b]oxirene-4,4-dioxide (13)

To a solution of 1.5 g (5.64 mmole) of 12 in 25 ml of CHCl₃ was added 6.8 g (19.4 mmole) of 50-60% MCPB portionwise causing an exothem and formation of a white solid. The mixture was stirred at room temperature overnight diluted with 100 ml methylene chloride and washed successively with 10% K₂CO₃ (4×50 ml), water (twice with 25 ml) and brine. The organic layer was then dried over MgSO₄ and evaporated to dryness to recover 1.47 g of an off white solid. ¹H NMR indicated that only one isomer is present. This solid was slurried in 200 ml of warm Et₂O and filtered to give 0.82 g (46%) of 13 as a white solid, mp 185-186.5° C.

Example 11 (3α,4β,5α)-3-Ethyl-4-hydroxy-5-phenyl-2,3,4,5-tetrahydro-benzothiepine-1,1-dioxide (14a), (3α,4β,5β) 3-Ethyl-4-hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (14b), and cis-3-Ethyl-5-phenyl-2,3,4,5-tetrahydro-benzothiepine-1,1-dioxide (15)

A mixture of 0.5 g (1.6 mole) of 13, 50 ml of acetic acid and 0.5 g of 10% Pd/C catalyst was hydrogenated with 70 psi hydrogen for 4 h. The crude reaction slurry was filtered and the filtrate was stirred with 150 ml of a saturated NaHCO₃ solution followed by 89 g of NaHCO₃ powder portionwise to neutralize the rest of acetic acid. The mixture was extracted with methylene chloride (4×25 ml), then the organic layer was dried over MgSO₄ and concentrated in vacuo to give 0.44 g (87%) of a voluminous white solid which was purified by HPLC (EtOAc-Hexane) to give 26.8 mg (6%) of 15 in the first fraction, 272 mg (54%) of 14a as a solid, mp 142-143.5° C., in the second fraction, and 35 mg (7%) of impure 14b in the third fraction.

Example 12 2-Ethyl-2-((2-Hydroxymethylphenyl)thiomethyl)hexenal (16)

A mixture of 5.0 g (0.036 mole) of 2-mercaptobenzyl alcohol, 6.4 g (0.032 mole) of 1, 3.6 g (0.036 mole) of triethylamine and 25 mL of 2-methoxyethyl ether was held at reflux for 7 h. Additional 1.1 g of mercaptobenzyl alcohol and 0.72 g of triethylamine was added to the reaction mixture and the mixture was held at reflux for additional 16 h. The reaction mixture was cooled and poured into 6N HCl and extracted with methylene chloride. The methylene chloride extract was washed twice with 10% NaOH, dried over MgSO₄ and concentrated in vacuo to give 9.6 g of residue. Purification by HPLC (20% EtOAc-hexane) gave 3.7 g (41%) of 16 as an oil.

Example 13 2-Ethyl-2-((2-formylphenyl)thiomethyl)hexenal (17)

A mixture of 3.7 g of 16, 5.6 g (0.026 mole) of pyridinium chlorochromate, 2 g of Celite and 30 mL of methylene chloride was stirred for 18 h and filtered through a bed of silica gel. The silica gel was eluted with methylene chloride. The combined methylene chloride eluant was purified by HPLC (20% ETOAc-hexane) to give 2.4 g (66%) of an oil.

Example 14 3-Butyl-3-ethyl-2,3-dihydrobenzothiepine (18)

A mixture of 2.6 g (0.04 mole) of zinc dust, 7.2 g (0.047 mole) of TiCl₃, and 50 mL of DME was held at reflux for 2 h and cooled to room temperature. To this mixture was added 2.4 g (8.6 mmole) of 17 in 20 mL of DME in 10 min. The reaction mixture was stirred at room temperature for 2 h and held at reflux for 1 h then was let standing at room temperature over weekend. The reaction mixture was poured into dilute HCl and was stirred with methylene chloride. The methylene chloride-water mixture was filtered through Celite. The methylene chloride layer was washed with brine, dried over MgSO₄, and concentrated in vacuo to give 3.0 g of a residue. Purification by HPLC gave 0.41 g (20%) of 18 as an oil in the early fraction.

Example 15 (1aα,2α,8bα) 2-Butyl-2-ethyl-1a,2,3,8b-tetrahydro-benzothiepino[4,5-b]oxirene-4,4-dioxide (19a) and (1aα,2β,8bα) 2-Butyl-2-ethyl-8b-phenyl-1a,2,3,8b-tetrahydro-benzothiepino[4,5-b]oxirene-4,4-dioxide (19b)

To a solution of 0.4 g of 0.4 g (1.6 mmole) of 18 in 30 mL of methylene chloride was added 2.2 g (3.2 mmole) of 50-60% MCPBA. The reaction mixture was stirred for 2 h and concentrated in vacuo. The residue was dissolved in 30 mL of CHCl₃ and was held at reflux for 18 h under N₂. The reaction mixture was stirred with 100 mL of 10% NaOH and 5 g of sodium sulfite. The methylene chloride layer was washed with brine, dried over MgSO₄ and concentrated in vacuo. The residue was purified by HPLC (20% EtOAc-hexane) to give a third fraction which was further purified by HPLC (10% EtOAc-hexane) to give 0.12 g of syrup in the first fraction. Recrystallization from hexane gave 0.08 g (17%) of 19a, mp 89.5-105.5° C. The mother liquor from the first fraction was combined with the second fraction and was further purified by HPLC to give additional 19a in the first fraction and 60 mg of 19b in the second fraction. Crystallization from hexane gave 56 mg of a white solid.

Example 16 3-Butyl-3-ethyl-4,5-dihydroxy-5-phenyl-2,3,4,5-tetrahydro-benzothiepine-1,1-dioxide (20)

This product was isolated along with 6b from hydrogenation of a mixture of 8a and 8b.

Example 17 3-Butyl-3-ethyl-4-hydroxy-5-phenylthio-2,3,4,5-tetrahydro-benzothiepine-1,1-dioxide (21)

A mixture of 25 mg (0.085 mmole) of 19b, 0.27 g (2.7 mmole) of thiophenol, 0.37 g (2.7 mmole) of potassium carbonate, and 4 mL of DMF was stirred at room temperature under N₂ for 19 h. The reaction mixture was poured into water and extracted with methylene chloride. The methylene chloride layer was washed successively with 10% NaOH and brine, dried over MgSO₄, and concentrated in vacuo to give 0.19 g of semisolid which contain substantial amounts of diphenyl disulfide. This material was purified by HPLC (5% EtOAc-hexane) to remove diphenyl disulfide in the first fraction. The column was then eluted with 20% EtOAc-hexane to give 17 mg of a first fraction, 4 mg of a second fraction and 11 mg of a third fraction which were three different isomers of 21, i.e. 21a, 21b, and 21c, respectively, by ¹H NMR and mass spectra.

Example 18

Alternative Synthesis of 6c and 6d

A. Preparation from 2-((2-Benzoylphenylthio)methyl)-2-ethylhexanal (2)

Step 1. 2-((2-Benzoylphenylsulfonyl)methyl)-2-ethylhexanal (44)

To a solution of 9.0 g (0.025 mole) of compound 2 in 100 ml of methylene chloride was added 14.6 g (0.025 mol) of 50-60% MCPBA portionwise. The reaction mixture was stirred at room temperature for 64 h then was stirred with 200 ml of 1 M potassium carbonate and filtered through Celite. The methylene chloride layer was washed twice with 300 ml of 1 M potassium carbonate, once with 10% sodium hydroxide and once with brine. The insoluble solid formed during washing was removed by filtration through Celite. The methylene chloride solution was dried and concentrated in vacuo to give 9.2 g (95%) of semisolid. A portion (2.6 g) of this solid was purified by HPLC(10% ethyl acetate-hexane) to give 1.9 g of crystals, mp 135-136° C.

Step 2. 2-((2-Benzylphenylsulfonyl)methyl)-2-ethylhexanal (45)

A solution of 50 g (0.13 mole) of crude 44 in 250 ml of methylene chloride was divided in two portions and charged to two Fisher-Porter bottles. To each bottle was charged 125 ml of methanol and 5 g of 10% Pd/C. The bottles were pressurized with 70 psi of hydrogen and the reaction mixture was stirred at room temperature for 7 h before being charged with an additional 5 g of 10% Pd/C. The reaction mixture was again hydrogenated with 70 psi of hydrogen for 7 h. This procedure was repeated one more time but only 1 g of Pd/C was charged to the reaction mixture. The combined reaction mixture was filtered and concentrated in vacuo to give 46.8 g of 45 as brown oil.

Step 3. (3α,4α,5α) 3-Butyl-3-ethyl-4-hydroxy-5-phenyl-2,3,4, 5-tetrahydrobenzothiepine-1,1-dioxide (6c), and (3α,4β,5β) 3-Butyl-3-ethyl-4-hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (6d)

To a solution of 27.3 g (73.4 mmole) of 45 in 300 ml of anhydrous THF cooled to 2° C. with an ice bath was added 9.7 g (73.4 mmole) of 95% potassium t-butoxide. The reaction mixture was stirred for 20 min, quenched with 300 ml of 10% HCl and extracted with methylene chloride. The methylene chloride layer was dried over magnesium sulfate and concentrated in vacuo to give 24.7 g of yellow oil. Purification by HPLC (ethyl acetate-hexane) yielded 9.4 g of recovered 45 in the first fraction, 5.5 g (20%) of 6c in the second fraction and 6.5 g (24%) of 6d in the third fraction.

B. Preparation from 2-hydroxydiphenylmethane

Step 1. 2-mercaptodiphenylmethane (46)

To a 500 ml flask was charged 16 g (0.33 mol) of 60% sodium hydride oil dispersion. The sodium hydride was washed twice with 50 ml of hexane. To the reaction flask was charged 100 ml of DMF. To this mixture was added a solution of 55.2 g (0.3 mol) of 2-hydroxydiphenylmethane in 200 ml of DMF in 1 h while temperature was maintained below 30° C. by an ice-water bath. After complete addition of the reagent, the mixture was stirred at room temperature for 30 min then cooled with an ice bath. To the reaction mixture was added 49.4 g (0.4 mole) of dimethyl thiocarbamoyl chloride at once. The ice bath was removed and the reaction mixture was stirred at room temperature for 18 h before being poured into 300 ml of water. The organic was extracted into 500 ml of toluene. The toluene layer was washed successively with 10% sodium hydroxide and brine and was concentrated in vacuo to give 78.6 g of a yellow oil which was 95% pure dimethyl O-2-benzylphenyl thiocarbamate. This oil was heated at 280-300° C. in a kugelrohhr pot under house vacuum for 30 min. The residue was kugelrohr distilled at 1 torr (180-280° C.). The distillate (56.3 g) was crystallized from methanol to give 37.3 g (46%) of the rearranged product dimethyl S-2-benzylphenyl thiocarbamate as a yellow solid. A mixture of 57 g (0.21 mole) of this yellow solid, 30 g of potassium hydroxide and 150 ml of methanol was stirred overnight then was concentrated in vacuo. The residue was diluted with 200 ml of water and extracted with ether. The aqueous layer was made acidic with concentrate HCl, The oily suspension was extracted into ether. The ether extract was dried over magnesium sulfate and concentrated in vacuo. The residue was crystallized from hexane to give 37.1 g (88%) of 2-mercaptodiphenylmethane as a yellow solid.

Step 2. 2-((2-Benzylphenylthio)methyl)-2-ethylhexanal (47)

A mixture of 60 g (03 mole) of yellow solid from step 1, 70 g (0.3 mole) of compound 1 from preparation 1, 32.4 g (0.32 mole) of triethylamine, 120 ml of 2-methoxyethyl ether was held at reflux for 6 hr and concentrated in vacuo. The residue was triturated with 500 ml of water and 30 ml of concentrate HCl. The organic was extracted into 400 ml of ether. The ether layer was washed successively with brine, 10% sodium hydroxide and brine and was dried over magnesium sulfate and concentrated in vacuo. The residue (98.3 g) was purified by HPLC with 2-5% ethyl acetate-hexane as eluent to give 2-((2-benzylphenylthio)methyl)-2-ethylhexanal 47 as a yellow syrup.

Step 3. 2-((2-Benzylphenylsulfonyl)methyl)-2-ethylhexanal (45)

To a solution of 72.8 g (0.21 mole) of yellow syrup from step 2 in 1 liter of methylene chloride cooled to 10° C. was added 132 g of 50-60% MCPBA in 40 min. The reaction mixture was stirred for 2 h. An additional 13 g of 50-60% MCPBA was added to the reaction mixture. The reaction mixture was stirred for 2 h and filtered through Celite. The methylene chloride solution was washed twice with 1 liter of 1 M potassium carbonate then with 1 liter of brine. The methylene chloride layer was dried over magnesium sulfate and concentrated to 76 g of 2-((2-benzylphenylsulfonyl)methyl)-2-ethylhexanal 45 as a syrup.

Step 4. (3α,4α,5α) 3-Butyl-3-ethyl-4-hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (6c), and (3α,4β,5β) 3-Butyl-3-ethyl-4-hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (6d)

Reaction of 45 with potassium t-butoxide according to the procedure in step 3 of procedure A gave pure 6c and 6d after HPLC.

Example 19 (3α,4β,5β) 3-Butyl-3-ethyl-4-hydroxy-8-methoxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (25) and (3α,4α,5α) 3-Butyl-3-ethyl-4-hydroxy-8-methoxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (26)

Step 1. Preparation of 2-((2-benzoyl-4-methoxy phenylthio)methyl)-2-ethylhexanal (22)

2-Hydroxy-4-methoxybenzophenone was converted to the dimethyl O-2-benzoyphenyl thiocarbamate by methods previously described in example 18. The product can be isolated by recrystallization from ethanol. Using this improved isolation procedure no chromatography was needed. The thermal rearrangement was performed by reacting the thiocarbamate(5 g) in diphenyl ether at 260° C. as previously described. The improved isolation procedure which avoided a chromatography step was described below.

The crude pyrolysis product was then heated at 65° C. in 100 ml of methanol and 100 ml of THF in the presence of 3.5 g of KOH for 4 h. After removing THF and methanol by rotary evaporation the solution was extracted with 5% NaOH and ether. The base layer was acidified and extracted with ether to obtain a 2.9 g of crude thiophenol product. The product was further purified by titrating the desired mercaptan into base with limited KOH. After acidification and extraction with ether pure 2-mercapto-4-methoxybenzophenone (2.3 g) was isolated.

2-mercapto-4-methoxybenzophenone can readily be converted to the 2-((2-benzoyl-4-methoxyphenylthio)methyl)-2-ethylhexanal (22) by reaction with 2-ethyl-2-(mesyloxymethyl)hexanal (1) as previously described.

Step 2. 2-((2-Benzoyl-5-methoxyphenylsulfonyl)methyl)-2-ethylhexanal (23)

Substrate 22 was readily oxidized to 2-((2-benzoyl-5-methoxyphenyl-sulfonyl)methyl)-2-ethylhexanal (23) as described in example 18.

Step 3. 2-((2-benzyl-5-methoxyphenylsulfonyl)methyl)-2-ethylhexanal (24)

Sulfone 23 was then reduced to 2-((2-benzyl-5-methoxyphenyl-sulfonyl)methyl) -2-ethylhexanal (24) as described in example 18.

Step 4. (3α,4β,5β) 3-Butyl-3-ethyl-4-hydroxy-8-methoxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (25) and (3α,4α,5α) 3-Butyl-3-ethyl-4-hydroxy-8-methoxy-5-phenyl-2,3,4, 5-tetrahydrobenzothiepine-1,1-dioxide (26)

A 3-neck flask equipped with a powder addition funnel, thermocouple and nitrogen bubbler was charged with 19.8 g (0.05 mole) of sulfone 24 in 100 ml dry THF. The reaction was cooled to −1.6° C. internal temperature by means of ice/salt bath. Slowly add 5.61 g (0.05 mole) of potassium t-butoxide by means of the powder addition funnel. The resulting light yellow solution was maintained at −1.6° C. After 30 min reaction 400 ml of cold ether was added and this solution was extracted with cold 10% HCl. The acid layer was extracted with 300 ml of methylene chloride. The organic layers were combined and dried over magnesium sulfate and after filtration stripped to dryness to obtain 19.9 g of product. ¹H nmr and glpc indicated a 96% conversion to a 50/50 mixture of 25 and 26. The only other observable compound was 4% starting sulfone 24.

The product was then dissolved in 250 ml of 90/10 hexane/ethyl acetate by warming to 50° C. The solution was allowed to cool to room temperature and in this way pure 26 can be isolated. The crystallization can be enhanced by addition of a seed crystal of 26. After 2 crystallizations the mother liquor which was now 85.4% 25 and has a dry weight of 8.7 g. This material was dissolved in 100 ml of 90/10 hexane/ethyl acetate and 10 ml of pure ethyl acetate at 40° C. Pure 25 can be isolated by seeding this solution with a seed crystal of 25 after storing it overnight at 0 C.

Example 20 (3α,4α,5α) 3-Butyl-3-ethyl-4,8-dihydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (27)

In a 25 ml round bottomed flask, 1 g of 26(2.5 mmoles) and 10 ml methylene chloride were cooled to −78° C. with stirring. Next 0.7 ml of boron tribromide(7.5 mmole) was added via syringe. The reaction was allowed to slowly warm to room temperature and stirred for 6 h. The reaction was then diluted with 50 ml methylene chloride and washed with saturated NaCl and then water. The organic layer was dried over magnesium sulfate. The product (0.88g) 27 was characterized by NMR and mass spectra.

Example 21

General Alkylation of phenol 27

A 25 ml flask was charged with 0.15 g of 27(0.38 mmole), 5 ml anhydrous DMF, 54 mg of potassium carbonate (0.38 mmole) and 140 mg ethyl iodide (0.9 mmole). The reaction was stirred at room temperature overnight. The reaction was diluted with 50 ml ethyl ether and washed with, water (25 ml) then 5% NaOH (20 ml) and then sat. NaCl. After stripping off the solvent the ethoxylated product 28 was obtained in high yield. The product was characterized by NMR and mass spectra. This same procedure was used to prepare products listed in table 1 from the corresponding iodides or bromides. For higher boiling alkyl iodides and bromides only one equivalent of the alkyl halide was used.

TABLE 1

Formula for Table 1 Compound No. R 27 H 26 Me 28 Et 29 hexyl 30 Ac 31 (CH₂) 6-N-pthalimide

Example 22 (3α,4α,5α) 3-Butyl-3-ethyl-4-hydroxy-7-hydroxyaxmino-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (37) and (3α,4β,5β) 3-Butyl-3-ethyl-4-hydroxy-7-hydroxyamino-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (38)

Step 1. Preparation of 2-chloro-5-nitrodiphenylmethane (32)

Procedure adapted from reference :Synthesis -Stuttgart 9 770-772 (1986) Olah G. Et al

Under nitrogen, a 3 neck flask was charged with 45 g (0.172 mole) of 2-chloro-5-nitrobenzophenone in 345 ml methylene chloride and the solution was cooled to ice/water temperature. By means of an additional funnel, 150 g(0.172 mole) of trifluoromethane sulfonic acid in 345 ml methylene chloride was added slowly. Next 30 g of triethylsilane (0.172 mole) in 345 ml methylene chloride was added dropwise to the chilled solution. Both addition steps (trifluoromethane sulfonic acid and triethylsilane) were repeated. After the additions were completed the reaction was allowed to slowly warm up to room temperature and stirred for 12 h under nitrogen. The reaction mixture was then poured into a chilled stirred solution of 1600 ml of saturated sodium bicarbonate. Gas evolution occurred. Poured into a 4 liter separatory funnel and separated layers. The methylene chloride layer was isolated and combined with two 500 ml methylene chloride extractions of the aqueous layer. The methylene chloride solution was dried over magnesium sulfate and concentrated in vacuo. The residue was recrystallized from hexane to give 39 g product. Structure 32 was confirmed by mass spectra and proton and carbon NMR.

Step 2. Preparation of 2-((2-benzyl-4-nitrophenylthio)methyl)-2-ethylhexanal (33)

The 2-chloro-5-nitrodiphenylmethane product 32 (40 g, 0.156 mole) from above was placed in a 2 liter 2 neck flask with water condenser. Next 150 ml DMSO and 7.18 g (0.156 mole) of lithium sulfide was added and the solution was stirred at 75° C. for 12 h. The reaction was cooled to room temperature and then 51.7 g of mesylate IV was added in 90 ml DMSO. The reaction mixture was heated to 80° C. under nitrogen. After 12 h monitored by TLC and added more mysylate if necessary.

Continued the reaction until the reaction was completed. Next the reaction mixture was slowly poured into a 1900 ml of 5% acetic aqueous solution with stirring, extracted with 4×700 ml of ether, and dried over MgSO4. After removal of ether, 82.7 g of product was isolated. The material can be further purified by silica gel chromatography using 95% hexane and 5% ethyl acetate. If pure mysylate was used in this step there was no need for further purification. The product 33 was characterized by mass spectra and NMR.

Step 3. Oxidation of the nitro product 33 to the sulfone 2-((2-benzyl-4-nitrophenylsulfonyl)methyl)-2-ethylhexanal (34)

The procedure used to oxidize the sulfide 33 to the sulfone 34 has been previously described.

Step 4. Reduction of 34 to 2-((2-benzyl-4-hydroxyaminophenylsulfonyl)methyl)-2-ethylhexanal (35)

A 15 g sample of 34 was dissolved in 230 ml of ethanol and placed in a 500 ml rb flask under nitrogen. Next 1.5 g of 10 wt. % Pd/C was added and hydrogen gas was bubbled through the solution at room temperature until the nitro substrate 34 was consumed. The reaction could be readily monitored by silica gel TLC using 80/20 hexane/EtOAc. Product 35 was isolated by filtering off the Pd/C and then stripping off the EtOH solvent. The product was characterized by NMR and mass spectra.

Step 5. Preparation of the 2-((2-benzyl-4-N,O-di-(t-butoxy-carbonyl)hydroxyaminophenylsulfonyl)methyl)-2-ethylhexanal (36).

A 13.35 g sample of 35 (0.0344 mole) in 40 ml of dry THF was stirred in a 250 ml round bottomed flask. Next added 7.52 g (0.0344 mole) of di-t-butyl dicarbonate in 7 ml THF. Heated at 60° C. overnight. Striped off THF and redissolved in methylene chloride. Extracted with 1% HCl; and then 5% sodium bicarbonate.

The product was further purified by column chromatography using 90/10 hexane/ethyl acetate and then 70/30 hexane/ethyl acetate. The product 36 was obtained (4.12 g) which appeared to be mainly the di-(t-butoxycarbonyl) derivatives by proton NMR.

Step 6. (3α,4α,5α) 3-Butyl-3-ethyl-4-hydroxy-7-hydroxyamino-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (37) and (3α,4β,5β) 3-Butyl-3-ethyl-4-hydroxy-7-hydroxyamino-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-l,l-dioxide (38)

A 250 ml 3-neck round bottomed flask was charged with 4 g of 36 (6.8 mmoles), and 100 ml of anhydrous THF and cooled to −78° C. under a nitrogen atmosphere. Slowly add 2.29 g potassium tert-butoxide(20.4 mmoles) with stirring and maintaining a −78° C. reaction temperature. After 1 h at −78° C. the addition of base was completed and the temperature was brought to −10° C. by means of a ice/salt bath. After 3 h at −10° C., only trace 36 remained by TLC. Next add 35 ml of deionized water to the reaction mixture at −10° C. and stirred for 5 min. Striped off most of the THF and added to separatory funnel and extracted with ether until all of the organic was removed from the water phase. The combined ether phases were washed with saturated NaCl and then dried over sodium sulfate. The only products by TLC and NMR were the two BOC protected isomers of 37 and 38. The isomers were separated by silica gel chromatography using 85% hexane and 15% ethyl acetate; BOC-37 (0.71 g) and BOC-38 (0.78. g).

Next the BOC protecting group was removed by reacting 0.87 g of BOC-38 (1.78 mmoles) with 8.7 ml of 4 M HCl (34.8 mmoles)in dioxane for 30 min. Next added 4.74 g of sodium acetate (34.8 mmoles) to the reaction mixture and 16.5 ml ether and stirred until clear. After transferring to a separatory funnel extracted with ether and water and then dried the ether layer with sodium sulfate. After removing the ether, 0.665 g of 38 was isolated. Isomer 37 could be obtained in a similar procedure.

Example 23 (3α,4α,5α) 3-Butyl-3-ethyl-7-(n-hexylamino)-4-hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (40) and (3α,4β,5β) 3-Butyl-3-ethyl-7-(n-hexylamino)-4-hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (41)

Step 1. 2-((2-Benzyl-4-(n-hexylamino)phenylsulfonyl)methyl)-2-ethylhexanal (39)

In a Fischer porter bottle weighed out 0.5 g of 34 (1.2 mmoles) and dissolved in 3.8 ml of ethanol under nitrogen. Next added 0.1 g of Pd/C and 3.8 ml of hexanal. Seal and pressure to 50 psi of hydrogen gas. Stirred for 48 h. After filtering off the catalyst and removing the solvent by rotary evaporation 39 was isolated by column chromatography (0.16 g) using. 90/10 hexane ethyl acetate and gradually increasing the mobile phase to 70/30 hexane/ethyl acetate. The product was characterized by NMR and mass spectra.

Step 2. (3α,4α,5α) 3-Butyl-3-ethyl-7-(n-hexylamino)-4-hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (40) and (3α,4β,5β) 3-Butyl-3-ethyl-7-(n-hexylamino)-4-hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (41)

A 2-neck, 25 ml round bottomed flask with stir bar was charged with 0.158 g 39 (0.335 mmole) and 5 ml anhydrous THF under nitrogen. Cool to −10° C. by means of a salt/water bath. Slowly add 0.113 g of potassium tert butoxide (0.335 mmole). After 15 min at −10° C. all of the starting material was consumed by TLC and only the two isomers 40 and 41 were observed. Next added 5 ml of chilled 10% HCl and stirred at −10° C. for 5 min. Transferred to a separatory funnel and extract with ether. Dried over sodium sulfate. Proton NMR of the dried product (0.143 g) indicated only the presence of the two isomers 40 and 41. The two isomers were separated by silica gel chromatography using 90/10 hexane ethyl acetate and gradually increasing the mobile phase to 70/30 hexane/ethyl acetate. 40 (53.2 mg); 41(58.9 mg).

Example 24

Quaternization of Amine Substrates 40 and 41

Amine products such as 40 and 41 can be readily alkylated to quaternary salts by reaction with alkyl halides. For example 40 in DMF with 5 equivalents of methyl iodide in the presence of 2,6 dimethyl lutidine produces the dimethylhexylamino quaternary salt.

Example 25 (3α,4β,5β) 3-Butyl-3-ethyl-4-hydroxy-5-(4-iodophenyl)-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (42)

In a 25 ml round bottomed flask 0.5 g (1.3 mmole) of 6d, 0.67 g of mercuric triflate were dissolved in 20 ml of dry methylene chloride with stirring. Next 0.34 g of Iodine was added and the solution was stirred at room temperature for 30 h. The reaction was then diluted with 50 ml methylene chloride and washed with 10 ml of 1 M sodium thiosulfate; 10 ml of saturated KI ; and dried over sodium sulfate. See Tetrahedron, Vol.50, No. 17, pp 5139-5146 (1994) Bachki, F. Et al.Mass spectrum indicated a mixture of 6d , mono iodide 42 and a diiodide adduct. The mixture was separated by column chromatography and 42 was characterized bt NMR and mass spectra.

Example 26 (3α,4β,5β) 3-Butyl-5-(4-carbomethoxyphenyl)-3-ethyl-4-hydroxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (43)

A 0.1 g sample of 42 (0.212 mmole), 2.5 ml dry methanol, 38 μl triethylamine (0.275 mmole), 0.3 ml toluene and 37 mg of palladium chloride (0.21 mmole) was charged to a glass lined mini reactor at 300 psi carbon monoxide. The reaction was heated at 100° C. overnight. The catalyst was filtered and a high yield of product was isolated. The product was characterized by NMR and mass spectra.

Note the ester functionalized product 43 can be converted to the free acid by hydrolysis.

Example 27 (3α,4α,5α) 3-Butyl-3-ethyl-4-hydroxy-7-methoxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (48), and (3α,4β,5β) 3-Butyl-3-ethyl-4-hydroxy-7-methoxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (49)

Step 1. 2-Mercapto-5-methoxybenzophenone (50)

Reaction of 66.2 g of 4-methoxythiophenol with 360 ml of 2.5 N n-butyllithium, 105 g of tetramethylethylenediamine and 66.7 g of benzonitrile in 600 ml cyclohexane according to the procedure in WO 93/16055 gave 73.2 g of brown oil which was kugelrohr distilled to remove 4-methoxythiophenol and gave 43.86 g of crude 50 in the pot residue.

Step 2. 2-((2-Benzoyl-4-methoxyphenylthio)methyl)-2-ethylhexanal (51)

Reaction of 10 g (0.04 mole) of crude 50 with 4.8 g (0.02 mole)of mesylate 1 and 3.2 ml (0.23 mole) of triethylamine in 50 ml of diglyme according to the procedure for the preparation of 2 gave 10.5 g of crude product which was purified by HPLC (5% ethyl acetate-hexane) to give 1.7 g (22%) of 51.

Step 3. 2-((2-Benzoyl-4-methoxyphenylsulfonyl)methyl)-2-ethyl-hexanal (52)

A solution of 1.2 g (3.1 mmoles) of 51 in 25 ml of methylene chloride was reacted with 2.0 g (6.2 mmoles) of 50-60% MCPBA according to the procedure of step 2 of procedure A in example 18 gave 1.16 g (90%) of 52 as a yellow oil.

Step 4. 2-((2-Benzyl-4-methoxyphenylsulfonyl)methyl)-2-ethylhexanal (53)

Hydrogenation of 1.1 g of 52 according to the procedure of step 3 of procedure A of example 18 gave 53 as a yellow oil (1.1 g).

Step 5. (3α,4α,5α) 3-Butyl-3-ethyl-4-hydroxy-7-methoxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (48), and (3α,4β,5β) 3-Butyl-3-ethyl-4-hydroxy-7-methoxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (49)

A solution of 1.1 g of 53, 0.36 g of potassium t-butoxide and 25 ml of anhydrous THF was held at reflux for 2 h and worked up as in step 4 of procedure A of example 18 to give 1.07 g of a crude product which was purified by HPLC to give 40 mg (4%) of 48 as crystals, mp 153-154° C. and 90 mg (8%) of 49 as solid, mp 136-140° C.

Example 28 5-Phenyl-2,3-dihydrospirobenzothiepine-3,1′-cyclohexane (57)

Step 1. 1-(Hydroxymethyl)-cyclohexanecarboxaldehyde (54)

To a cold (0° C. mixture of 100 g (0.891 mole) of cyclohexanecarboxaldehyde, 76.5 g of 37% of formaldehyde in 225 ml of methanol was added dropwise 90 ml of 1 N Sodium hydroxide in 1 h. The reaction mixture was stirred at room temperature over 48 then was evaporated to remove methanol. The reaction mixture was diluted with water and extracted with methylene chloride. The organic layer was washed with water, brine, and dried over sodium sulfate and concentrated under vacuum to give 75 g (59.7%) of thick oil. Proton NMR and mass spectra were consistent with the product.

Step 2. 1-(mesyloxymethyl)cyclohexanecarboxaldehyde (55)

To a cold (0° C.) mixture of alcohol 54 (75 g, 0.54 mole) and 65.29 g (0.57 mole) of methanesulfonyl chloride in 80 ml of methylene chloride was added a solution of pyridine (47.96 g, 0.57 mole) in 40 ml of methylene chloride. The reaction mixture was stirred at room temperature for 18 h then quenched with water, acidified with conc. HCl and extracted with methylene chloride. The organic layer was washed with water, brine, and dried over sodium sulfate and concentrated under vacuum to give 91.63 g (77.8%) of thick oil. Proton NMR and mass spectra were consistent with the product.

Step 3. 1-((2-Benzoylphenylthio)methyl)cyclohexanecarboxaldehyde (56)

A mixture of 69 g (0.303 mole) of 2-mercaptobenzophenone, 82 g (0.303 mole) of mesylate 55, 32 g of triethylamine, and 150 ml of diglyme was stirred and held at reflux for 24 h. The mixture was cooled, poured into dil. HCl and extracted with methylene chloride. The organic layer was washed with 10% NaOH, water, brine, and dried over sodium sulfate and concentrated under vacuum to remove excess diglyme. This was purified by silica gel flush column (5% EtOAc: Hexane) and gave 18.6 g (75.9%) of yellow oil. Proton NMR and mass spectra were consistent with the product.

Step 4. 5-Phenyl-2,3-dihydrospirobenzothiepine-3,1′-cyclohexane (57)

To a mixture of 6.19 g of zinc dust and 100 ml of dry DME was added TiCl₃(16.8 g, 0.108 mole). The reaction mixture was heated to reflux for 2 h. A solution of compound 56 (8.3 g, 0.023 mole) in 50 ml of DME was added dropwise to the reaction mixture in 1 h and the mixture was held at reflux for 18 h. The mixture was cooled, poured into water and extracted with ether. The organic layer was washed with water, brine, and dried over sodium sulfate, filtered through celite and concentrated under vacuum. The residue was purified by HPLC (10% EtOAc: Hexane) to give 4.6 g (64%) of white solid, mp 90-91° C. Proton and carbon NMR and mass spectra were consistent with the product.

Example 29 8b-Phenyl-1a,2,3,8b-tetrahydrospiro(benzothiepino[4,5-b]oxirene-2,1′-cyclohexane)-4,4-dioxide (58)

To a solution of 57 (4.6 g, 15 mmole) in 50 ml chloroform under nitrogen was added 55% MCPBA (16.5 g, 52.6 mmole) portionwise with spatula. The reaction was held at reflux for 18 h and washed with 10% NaOH(3×), water, brine, and dried over sodium sulfate and concentrated under vacuum to give 5 g of crude product. This was recrystallized from Hexane/EtOAc to give 4.31 g (81%) of yellow solid, mp 154-155° C. Proton and carbon NMR and mass spectra were consistent with the product.

Example 30 trans-4-Hydroxy-5-phenyl-2,3,4,5-tetrahydro spiro(benzothiepine-3,1′-cyclohexane)-1,1-dioxide (59)

A mixture of 0.5 g (1.4 mmoles) of 58, 20 ml of ethanol, 10 ml of methylene chloride and 0.4 g of 10% Pd/C catalyst was hydrogenated with 70 psi hydrogen for 3 h at room temperature. The crude reaction slurry was filtered through Celite and evaporated to dryness. The residue was purified by HPLC (10% EtOAc-Hexane, 25% EtOAc-Hexane). The first fraction was 300 mg (60%) as a white solid, mp 99-100° C. Proton NMR showed this was a trans isomer. The second fraction gave 200 mg of solid which was impure cis isomer.

Example 31 cis-4-Hydroxy-5-phenyl-2,3,4,5-tetrahydro spiro(benzothiepine-3,1′-cyclohexane)-1,1-dioxide (60)

To a solution of 0.2 g (0.56 mmole) of 59 in 20 ml of CH₂C₂, was added 8 g of 50% NaOH and one drop of Aliquat-336 (methyltricaprylylammonium chloride) phase transfer catalyst. The reaction mixture was stirred for 10 h at room temperature. Twenty g of ice was added to the mixture and the mixture was extracted with CH₂Cl₂ (3×10 ml) washed with water, brine and dried over MgSO₄ and concentrated in vacuo to recover 0.15 g of crude product. This was recrystallized from Hexane/EtOAc to give 125 mg of white crystal, mp 209-210° C. Proton and carbon NMR and mass spectra were consistent with the product.

Example 32 (3α,4α,5α) 3-Butyl-3-ethyl-4-hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine (61), and (3α,4β,5β) 3-Butyl-3-ethyl-4-hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine (62)

To a solution of 0.5 g (1.47 mmole) of compound 47 in 5 ml of anhydrous THF was added 0.17 g (1.47 mmole) of 95% potassium t-butoxide. The reaction mixture was stirred at room temperature for 18 h and quenched with 10 ml of 10% HCl. The organic was extracted into methylene chloride. The methylene chloride extract was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by HPLC (2% EtOAc-hexane) to give 47 mg of 61 in the second fraction and 38 mg of 62 in the third fraction. Proton NMR and mass spectra were consistent with the assigned structures.

Example 33 (3α,4α,5α) 3-Butyl-3ethyl-4-hydroxy-7-amino-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (63) and (3α,4β,5β) 3-Butyl-3-ethyl-4-hydroxy-7-amino-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (64)

An autoclave was charged with 200 mg of 37 in 40 cc ethanol and 0.02 g 10% Pd/C. After purging with nitrogen the clave was charged with 100 psi hydrogen and heated to 55° C. The reaction was monitored by TLC and mass spec and allowed to proceed until all of 37 was consumed. After the reaction was complete the catalyst was filtered and the solvent was removed in vacuo and the only observable product was amine 63. This same procedure was used to produce 64 from 38.

Example 34 (3α,4α,5α) 3-Butyl-3-ethyl-4-hydroxy-7-methoxy-5-(3′-methoxyphenyl) -2,3,4, 5-tetrahydrobenzothiepine-1,1-dioxide (65), and (3α,4β,5β) 3-Butyl-3-ethyl-4-hydroxy-7-methoxy-5-(3′-methoxyphenyl)-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (66)

Alkylation of e-methoxyphenol with 3-methoxybenzyl chloride according to the procedure described in J. Chem. Soc, 2431 (1958) gave 4-methoxy-2-(3′-methoxybenzyl)phenol in 35% yield. This material was converted to compound 65, mp 138.5-141.5° C., and compound 66, mp 115.5-117.5° C., by the procedure similar to that in Example 18 method B.

Example 35 (3α,4α,5α) 3-Butyl-3-ethyl-4-hydroxy-7-methoxy-5-(3′-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (67), and (3α,4β,5β) 3-Butyl-3-ethyl-4-hydroxy-7-methoxy-5-(3′-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (68)

Alkylation of 4-methoxyphenol with 3-(trifluoromethyl)benzyl chloride according to the procedure described in J. Chem. Soc. 2431 (1958) gave 4-methoxy-2-(3′-(trifluoromethyl)benzyl)phenol. This material was converted to compound 67, mp 226.5-228° C., and compound 68, mp 188-190° C., by the procedure similar to that in Example 18 method B.

Example 36 (3α,4α,5α) 3-Butyl-3-ethyl-5-(4′-fluorophenyl) -4-hydroxy-7-methoxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (69), and (3α,4β,5β) 3-Butyl-3-ethyl-5-(4′-fluorophenyl)-4-hydroxy-7-methoxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (70).

Alkylation of 4-methoxyphenol with 4-fluorobenzyl chloride according to the procedure described in J. Chem. Soc, 2431 (1958) gave 4-methoxy-2-(4′-fluorobenzyl)phenol. This material was converted to compound 69 and compound 70 byu the procedure similar to that in Example 18 method B.

Example 37 (3α,4α,5α) 3-Butyl-3-ethyl-5-(3′-fluorophenyl)-4-hydroxy-7-methoxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (71), and (3α,4β,5β) 3-Butyl-3-ethyl-5-(3′-fluorophenyl)-4-hydroxy-7-methoxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (72)

Alkylation of 4-methoxyphenol with 3-fluorobenzyl chloride according to the procedure described in J. Chem. Soc, 2431 (1958) gave 4-methoxy-2-(3′-fluorobenzyl)phenol. This material was converted to compound 71 and compound 72 by the procedure similar to that in Example 18 method B.

Example 38 (3α,4α,5α) 3-Butyl-3-ethyl-5-(2′-fluorophenyl)-4-hydroxy-7-methoxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (73), and (3α,4β,5β) 3-Butyl-3-ethyl-5-(2′-fluorophenyl)-4-hydroxy-7-methoxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (74)

Alkylation of 4-methoxyphenol with 2-fluorobenzyl chloride according to the procedure described in J. Chem. Soc, 2431 (1958) gave 4-methoxy-2-(2′-fluorobenzyl)phenol. This material was converted to compound 73 and compound 74 by the procedure similar to that in Example 18 method B.

Example 39 (3α,4α,5α) 3-Butyl-7-bromo-3-ethyl-4-hydroxy-5-(3′-methoxyphenyl) -2,3,4, 5-tetrahydrobenzothiepine-1,1-dioxide (75), and (3α,4β,5β) 3-Butyl-7-bromo-3-ethyl-4-hydroxy-5-(3′-methoxyphenyl)-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (76)

Alkylation of 4-bromophenol with 3-methoxybenzyl chloride according to the procedure described in J. Chem. Soc, 2431 (1958) gave 4-bromo-2-(3′-methoxybenzyl)phenol. This material was converted to compound 75, mp 97-101.5° C., and compound 76, mp 102-106° C., by the procedure similar to that in Example 18 method B.

Example 40 (3α,4α,5α) 3-Butyl-3-ethyl-7-fluoro-5-(4′-fluorophenyl)-4-hydroxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (77), and (3α,4β,5β) 3-Butyl-3-ethyl-7-fluoro-5-(4′-fluorophenyl)-4-hydroxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (78)

Alkylation of 4-fluorophenol with 4-fluorobenzyl chloride according to the procedure described in J. Chem. Soc, 2431 (1958) gave 4-fluoro-2-(4′-fluorobenzyl)phenol. This material was converted to compound 77, mp 228-230° C., and compound 78, mp 134.5-139° C., by the procedure similar to that in Example 18 method B.

Example 41 (3α,4α,5α) 3-Butyl-3-ethyl-7-fluoro-4-hydroxy-5-(3′-methoxyphenyl)-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (79), and (3α,4β,5β) 3-Butyl-3-ethyl-7-fluoro-40hydroxy-5-(3′-methoxyphenyl)-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (80)

Alkylation of 4-fluorophenol with 3-methoxybenzyl chloride according to the procedure described in J. Chem. Soc, 2431 (1958) gave 4-fluoro-2-(3′-methoxybenzyl)phenol. This material was converted to compound 79, as a solid and compound 80, mp 153-155° C., by the procedure similar to that in Example 18 method B.

Example 42 (3α,4β,5β) 3-Butyl-3-ethyl-5-(4′-fluorophenyl)-4-hydroxy-7-methylthio-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (81)

A mixture of 0.68 (1.66 mmol) of compound 77, 0.2 g (5 mmol) of sodium methanethiolate and 15 ml of anhydrous DMF was stirred at room temperature for 16 days. The reaction mixture was dilute with ether and washed with water and brine and dried over M_(g)SO₄. The ether solution was concentrated in vacuo. The residue was purified by HPLC (20% ethyl acetate in hexanes). The first fraction was impure (3α,4α,5α) 3-butyl-3-ethyl-4-hydroxy-7-methylthio-5-(4′-fluorophenyl)-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide. The second fraction was compound 81, mp 185-186.5° C.

Example 43 (3α,4β,5β) 3-Butyl-3-ethyl-5-(4′-fluorophenyl)-4-hydroxy-7-(1-pyrrolidinyl)-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (82)

A mixture of 0.53 g (1.30 mmol) of compound 78 and 5 ml of pyrrolidine was held at reflux for 1 h. The reaction mixture was diluted with ether and washed with water and brine and dried over M_(g)SO₄. The ether solution was concentrated in vacuo. The residue was crystallized from ether-hexanes to give compound 82, mp 174.5-177° C.

Example 44 (3α,4β,5β) 3-Butyl-3-ethyl-5-(4′-fluorophenyl)-4-hydroxy-7-(1-morpholinyl)-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (83)

A mixture of 0.4 g (0.98 mmol) of compound 78 and 5.0 g (56 mmol) of morpholine was held at reflux for 2 h and concentrated in vacuo. The residue was diluted with ether (30 ml) and washed with water and brine and dried over M_(g)SO₄. The ether solution was concentrated in vacuo. The residue was recrystallized from ether-hexanes to give compound 83, mp 176.5-187.5° C.

Example 45 (3α,4α,5α) 3-Butyl-3-ethyl-5-(4′-fluorophenyl) -4-hydroxy-7-methyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (84), and (3α,4β,5β) 3-Butyl-3-ethyl-5-(4′-fluorophenyl)-4-hydroxy-7-methyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (85)

Alkylation of 4-methylphenol with 4-fluorobenzyl chloride according to the procedure described in J. Chem. Soc, 2431 (1958) gave 4-methyl-2-(40′-fluorobenzyl)phenol). This material was converted to compound 84 and compound 85 by the procedure similar to that in Example 18 method B.

Example 46 (3α,4β,5β) 3-Butyl-3-ethyl-4-hydroxy-5-(4′-hydroxyphenyl)-7-methoxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (86), and (3α,4β,5β) 3-Butyl-3-ethyl-4,7-dihydroxy-5-(4′-hydroxyphenyl)-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (87)

To a solution of 0.52 (1.2 mmol) of compound 66 in 20 ml of methylene chloride was added 1.7 g (6.78 mmol) of born tribromide. The reaction mixture was cooled to −78° C. and was stirred for 4 min. An additional 0.3 ml of boron tribromide was added to the reaction mixture and the reaction mixture was stirred at −78° C. for 1 h and quenced with 2 N HCl. The organic was extracted into ether. The ether layer was washed with brine, dried over M_(g)SO₄, and concentrated in vacuo. The residue (0.48 g) was purified by HPLC (30% ethyl acetate in hexanes). The first fraction was 0.11 g of compound 86 as a white solid, mp 171.5-173° C. The second fraction was crystallized from chloroform to give 0.04 g of compound 87 as a white solid, mp 264° C. (dec).

Example 47 (3α,4β,5β) 3-Butyl-3-ethyl-4,7-dihydroxy-5-(4′-fluorophenyl)-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (88)

Reaction of compound 70 with excess boron tribromide at room temperature and worked up as in Example 46 gave compound 88 after an HPLC purification.

Example 48 (3α,4β,5β) 3-Butyl-3-ethyl-5-(4′-fluorophenyl)-4-hydroxy-7- (1-azetidinyl) -2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (89)

A mixture of 0.20 g (0.49 mmol) of compound 78, and 2.0 g (35 mmol) of aztidine was held at reflux for 3 h and concentrated in vacuo. The residue was diluted with ether (30 ml) and washed with water and brine and dried MgSO4. The ether solution was concentrated on a steam bath. The separated crystals were filtered to give 0.136 g of 89 as prisms, mp 196.5-199.5° C.

Example 49 (3α,4α,5α) 3-Butyl-3-ethyl-5-(3′-methoxyphenyl)-4-hydroxy-7-methylthio-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (90), (3α,4β,5β) 3-Butyl-3-ethyl-5-(3′-methoxyphenyl)-4-hydroxy-7-methylthio-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (91)

A mixture of 0.4 g (0.95 mmol) of compound 79, 0.08 g (1.14 mmol) of sodium methanethiolate and 15 ml of anhydrous DMF was stirred at 60° C. for 2 h. An additional 1.4 mmol of sodium methanethiolate was added to the reaction mixture and the mixture was stirred at 60° C. for an additional 2 h. The reaction mixture was triturated with 100 ml of water and extracted methylene chloride. The methylene chloride water mixture was filtered through Celite and the methylene chloride layer was dried over M_(g)SO₄ and concentrated in vacuo. The first fraction (0.1 g) was compound 90, mp 117-121° C. The second fraction (0.16 g) was compound 91, mp 68-76° C.

Example 50 Preparation of polyethyleneglycol functionalized benzothiepine A

A 50 ml rb flash under a nitrogen atmosphere was charged with 0.54 g of M-Tres-5000 (Polyethyleneglycol Tresylate [methoxy-PEG-Tres,MW 5000] purchased from Shearwater Polymers Inc., 2130 Memorial Parkway, SW, Huntsville, Ala. 35801), 0.055 g Compound No. 136, 0.326 C_(s)CO₃ and 2cc anhydrous acetonitrile. The reaction was stirred at 30 C. for 5 days and then the solution was filtered to remove salts. Next, the acetonitrile was removed under vacuum and the product was dissolved in THF and then precipitated by addition of hexane. The polymer precipitate was isolate by filtration from the solvent mixture (THF/hexane). This precipitation procedure was continued until no Compound No. 136 was detected in the precipitated product (by TLC SiO2). Next, the polymer precipitate was dissolved in water and filtered and the water soluble polymer was dialyzed for 48 hours through a cellulose dialysis tube (Spectrum® 7 ,45 mm×0.5 ft, cutoff 1,000 MW). The polymer solution was then removed from the dialysis tube and lyophilized until dried. The NMR was consistent with the desired product A and gel permeation chromatography indicated the presence of a 4500 MW polymer and also verified that no free Compound No. 136 was present. This material was active in the IBAT in vitro cell assay.

Example 51

Preparation of Compound 140

A 2-necked 50 ml round bottom Flask was charged with 0.42 g of Tres-3400 (Polyethyleneglycol Tresylate [Tres-PEG-Tres,MW 3400] purchased from Shearwater Polymers Inc., 2130 Memorial Parkway, SW, Huntsville, Ala. 35801), 0.1 potassium carbonate, 0.100 g of Compound No. 111 and 5 ml anhydrous DMF. Stir for 6 days at 27° C. TLC indicated the disappearance of the starting Compound No. 111. The solution was transferred to a separatory funnel and diluted with 50 cc methylene chloride and then extracted with water. The organic layer was evaporated to dryness by means of a rotary evaporator. Dry wgt. 0.4875 g. Next, the polymer was dissolved in water and then dialyzed for 48 hours at 40° C. through a cellulose dialysis tube (spectrums® 7, 45 mm×0.5 ft, cutoff 1,000 MW). The polymer solution was then removed from the dialysis tube and lyophilized until dried 0.341 g). NMR was consistent with the desired product B.

Example 52

A 10 cc vial was charged with 0.21 g of Compound No. 136 (0.5 mmoles), 0.17g (1.3 mmoles)potassium carbonate, 0.6g (1.5 mmoles) of 1,2-bis-(2-iodoethoxy)-ethane and 10 cc DMF. The reaction was stirred for 4 days at room temperature and then worked up by washing with ether/water. The ether layer was stripped to dryness and the desired product Compound No. 134 was isolated on a silica gel column using 80/20 hexane ethyl acetate.

Example 53

Example 54

A two necked 25 ml round bottom Flask was charged with 0.5 g (1.24 mmoles) of 69462, 13 mls of anhydrous DMF, 0.055 g of 60% NaH dispersion and 0.230 g (0.62 mmoles) of 1,2-Bis [2-iodoethoxylethane] at 10° C. under nitogen. Next, the reaction was slowly heated to 40° C. After 14 hours all of the Compound No. 113 was consumed and the reaction was cooled to room temperature and extracted with ether/water. The ether layer was evaporated to dryness and then chromatographed on Silicage (80/20 ethyl acetate/hexane). Isolated Compound No. 112 (0.28 g) was characterized by NMR and mass spec.

Example 55

In a 50 ml round bottom Flask, add 0.7 g (1.8 mmoles) of Compound No. 136, 0.621 g of potassium carbonate, 6 ml DMF, and 0.33 g of 1,2-Bis[2-iodoethoxylethane]. Stir at 40° C. under nitrogen for 12 hours. The workup and isolation was the same procedure for Compound No. 112.

Examples 56 and 57 (Compound Nos. 131 and 137)

The compositions of these compounds are shown in Table 3.

The same procedure as for Example 55 except appropriate benzothiepine was used.

Example 58 (Compound No. 139)

The composition of this compound is shown in Table 3. Same procedure as for Example 55 with appropriate benzothiepine 1,6 diiodohexane was used instead of 1,2-Bis [2-iodoethoxylethane].

Example 59 (Compound No. 101)

This compound is prepared by condensing the 7-NH₂ benzothiepine with the 1,12-dodecane dicarboxylic acid or acid halide.

Example 60 (Compound No. 104)

2-Chloro-4-nitrobenzophenone is reduced with triethylsilane and trifluoromethane sulfonic acid to 2-chloro-4-nitrodiphenylmethane 32. Reaction of 32 with lithium sulfide followed by reacting the resulting sulfide with mesylate IV gives sulfide-aldehyde XXIII. Oxidation of XXIII with 2 equivalents of MCPBA yields sulfone-aldehyde XXIV (see Scheme 5). Reduction of the sulfone-aldehyde XXV formaldehyde and 100 psi hydrogen and 55 C. for 12 hours catalyzed by palladium on carbon in the same reaction vessel yields the substituted dimethylamine derivative XXVIII. Cyclization of XXVII with potassium t-butoxide yields a mixture of substituted amino derivatives of this invention Compound No. 104.

Example 61

A 1 oz. Fisher-porter bottle was charged with 0.14 g (0.34 mmoles) of 70112, 0.97 gms (6.8 mmoles) of methyl iodide, and 7 ml of anhydrous acetonitrile. Heat to 50° C. for 4 days. The quat. Salt Compound No. 192 was isolated by concentrating to 1 cc acetonitrile and then precipitating with diethyl ether.

Example 62

A 0.1 g (0.159 mmoles) sample of Compound No. 134 was dissolved in 15 ml of anhydrous acetonitrile in a Fischer-porter bottle and then trimethylamine was bubbled through the solution for 5 minutes at 0° C. and then capped and warmed to room temperature. The reaction was stirred overnight and the desired product was isolated by removing solvent by rotary evaporation.

Example 63 (Compound No. 295)

Sodium Hydride 60% (11 mg, 0.27 mmoles) in 1 cc of acetonitrile at 0° C. was reacted with 0.248 mmoles (0.10 g) of Compound No. 54 in 2.5 cc of acetonitrile at 0° C. Next, 0. (980 g 2.48 mmoles) of 1,2-Bis[2-iodoethoxylethane]. After warming to room temperature, stir for 14 hours. The product was isolated by column chromatography.

Example 64 (Compound No. 286)

Following a procedure similar to the one described in Example 86, infra (see Compound No. 118), the title compound was prepared and purified as a colorless solid; mp 180-181° C.; ¹H NMR (CHCl₃) δ0.85 (t, J=6 Hz, 3H_(—), 0.92 (t, J=6 Hz, 3H), 1.24-1.42 (m, 2H), 1.46-1.56 (m, 1H), 1.64-1.80 (m, 1H), 2.24-2.38 (m, 1H), 3.15 (AB, J_(AB)=15 Hz, Δv=42 Hz, 2H), 4.20 (d, J=8 Hz, 1H), 5.13 (s, 2H), 5.53 (s, 1H), 6.46 (s, 1H), 6.68 (s, 1H), 7.29-7.51 (m, 10H), 7.74 (d, J=8 Hz, 1H), 8.06 (d, J=8 Hz, 1H). FABMS m/z 494 (M+H), HRMS calcd for (M+H) 494.2001, found 494.1993. Anal. Calcd. for C₂₈H₃₁NO₅S: C, 68.13; H, 6.33; N, 2.84. Found: C, 68.19; H, 6.56; N, 2.74.

Example 65 (Compound No. 287)

Following a procedure similar to the one described in Example 89, infra (see Compound No. 121), the title compound was prepared and purified as a colorless solid: mp 245-246° C., ¹H NMR (CDCl₃) δ0.84 (t, J=6 Hz, 3H), 0.92 (t, J=6 Hz, 3H), 1.28, (d, J=8 Hz, 1H), 1.32-1.42 (m, 1H), 1.48-1.60 (m, 1H), 1.64-1.80 (m, 1H), 2.20-2.36 (m, 1H), 3.09 (AB, J_(AB)=15 Hz, Δv=42 Hz, 2H), 3.97 (bs, 2H), 4.15 (d, J=8 Hz, 1H), 5.49 (s, 1H), 5.95 (s, 1H), 6.54 (d, J=7 Hz, 1H), 7.29-7.53 (m, 5H), 7.88 (d, J=8 Hz, 1H); ESMS 366 (M+Li). Anal. Calcd. for C₂₀H₂₅NO₃S: C, 66.82; H, 7.01; N, 3.90. Found: C, 66.54; H, 7.20; N, 3.69.

Example 66 (Compound No. 288)

Following a procedure similar to the one described in Example 89, infra (see Compound No. 121), the title compound was prepared and purified by silica gel chromatography to give the desired product as a colorless solid: mp 185-186° C.; ¹H NMR (CDCl₃) δ1.12 (s, 3H), 1.49 (s, 3H), 3.00 (d, J=15 Hz, 1H), 3.28 (d, J=15 Hz, 1H), 4.00 (s, 1H), 5.30 (s, 1H), 5.51 (s, 1H), 5.97 (s, 1H), 6.56 (dd, J=2.1, 8.4 Hz, 1H), 7.31-7.52 (m, 5H), 7.89 (d, J=8.4 Hz, 1H). MS (FAB+) (M+H) m/z 332.

Example 67 (Compound No. 289)

Following a procedure similar to the one described in Example 89 (see Compound No. 121), the title compound was prepared and purified by silica gel chromatography to give the desired product as a white solid: mp 205-206° C.; ¹H NMR (CDCl₃) δ0.80-0.95 (m, 6H), 1.10-1.70 (m, 7H), 2.15 (m, 1H), 3.02 (d, J=15.3 Hz, 2H), 3.15 (d, J=15.1 Hz, 2H), 3.96 (s, br, 2H), 4.14 (d, J=7.8 Hz, 1H), 5.51 (s, 1H), 5.94 (d, J=2.2, 1H), 6.54 (dd, J=8.5, 2.2 Hz, 1H), 7.28-7.50 (m, 6H), 7.87 (d, J=8.5 Hz, 1H), MS (FAB): m/z 388 (M+H).

Example 68 (Compound No. 290)

Following a procedure similar to the one described in Example 89, infra (see Compound No. 121), the title compound was prepared and purified as a colorless solid: mp=96-98° C., ¹H NMR (CDCl₃) δ0.92 (t, J=7 Hz, 6H), 1.03-1.70 (m, 11H), 2.21 (t, J=8 Hz, 1H), 3.09 (AB, J_(AB)=−18 Hz, Δv=38 Hz, 2H), 3.96 (bs, 2H), 4.14 (d, J=7 Hz, 1H), 5.51 (s, 1H), 5.94 (s, 1H), 6.56 (d, J=9 Hz, 1H), 7.41-7.53 (m, 6H), 7.87 (d, J=8 Hz, 1H); FABMS m/z 416 (M+H).

Example 69

Following a procedure similar to the one described in Example 86, infra (see Compound No. 118), the title compound was prepared and purified as a colorless solid: ¹H NMR (CDCl₃) δ0.91 (t, J=7 Hz, 6H), 1.02-1.52 (m, 11H), 1.60-1.70 (m, 1H), 2.23 (t, J=8 Hz, 1H), 3.12 (AB, J_(AB)=18 Hz, Δv=36 Hz, 2H), 4.18 (d, J=7 Hz, 1H), 5.13 (s, 2H), 5.53 (s, 1H), 6.43 (s, 1H), 6.65 (s, 1H), 7.29-7.52 (m, 10H), 7.74 (d, J=9 Hz, 1H), 8.03 (d, J=8 Hz, 1H); ESMS m/z 556 (M+Li).

Example 70 (Compound No. 292)

Following a procedure similar to the one descried in Example 89, infra (see Compound No. 121), the title compound was prepared and purified as a colorless solid: mp=111-112.5° C., ¹H NMR (CDCl₃) δ0.90 (t, J=8 Hz, 6H), 1.03-1.50 (m, 10H), 1.55-1.70 (m, 2H), 2.18 (t, J=12 Hz, 2H), 3.07 (AB, J_(AB)=15 Hz, Δv=45 Hz, 2H), 4.09 (bs, 2H), 5.49 (s, 1H), 5.91 (s, 1H), 6.55 (d, J=9 Hz, 1H), 7.10 (t, J=7 Hz, 2H), 7.46 (t, J=6 Hz, 2H), 7.87 (d, J=9 Hz, 1H).

Example 71 (Compound No. 293)

During the preparation of Compound No. 290 from Compound No. 291 using BBr₃, the title compound was isolated: ¹H NMR (CDCl₃) δ0.85 (t, J=6 Hz, 6H), 0.98-1.60 (m, 10H), 1.50-1.66 (m, 2H), 2.16 (t, J=8 Hz, 1H), 3.04 (AB, J_(AB)=15 Hz, Δv=41 Hz, 2H), 4.08 (s, 1H), 4.12 (s, 1H), 5.44 (s, 1H), 5.84 (s, 1H), 6.42 (d, J=9 Hz, 1H), 7.12 (d, J=8 Hz, 2H), 7.16-7.26 (m, 10H), 7.83 (d, J=8 Hz, 1H); ESMS m/z 512 (M+Li).

Example 72 (Compound No. 294)

Following a procedure similar to the one described in Example 60 (Compound No. 104), the title compound was prepared and purified as a colorless solid: ¹H NMR (CDCl₃) δ0.90 (t, J=6 Hz, 6H), 1.05-1.54 (m, 9H), 1.60-1.70 (m, 1H), 2.24 (t, J=8 Hz, 1H), 2.80 (s, 6H), 3.05 (AB, J_(AB)=15 Hz, Δv=42 Hz, 2H), 4.05-4.18 (m, 2H), 5.53 (s, 1H), 5.93 (s, 1H), 6.94 (d, J=9 Hz, 1H), 7.27-7.42 (m, 4H), 7.45 (d, J=8 Hz, 2H), 7.87 (d, J=9 Hz, 1H); ESMS m/z 444 (M+H).

Structures of the compounds of Examples 33 to 72 are shown in Tables 3 and 3A.

Examples 73-79, 87, 88 and 91-102

Using in each instance a method generally described in those of Examples 1 to 72 appropriate to the substituents to be introduced, compounds were prepared having the structures set forth in Table 3. The starting materials illustrated in the reaction schemes shown above were varied in accordance with principles of organic synthesis well known to the art to introduce the indicated substituents in the 4- and 5-positions (R³, R⁴, R⁵, R⁶) and in the indicated position on the benzo ring (R^(x)).

Structures of the the compounds produced in Examples 73-102 are set forth in Tables 3 and 3A.

Examples 80-84 Preparation of 115, 116, 111, 113

Preparation of 4-chloro-3-[4-methoxy-phenylmethyl]-nitrobenzene.

In a 500 ml 2-necked rb flask weigh out 68.3 gms phosphorus pentachloride (0.328 mole 1.1 eq). Add 50 mls chlorobenzene. Slowly add 60 gms 2-chloro-5-nitrobenzoic acid (0.298 mole). Stir at room temp overnight under N2 then heat 1 hr at 50° C.

Remove chlorobenzene by high vacuum. Wash residue with hexane. Dry wt=55.5 gms.

In the same rb flask, dissolve acid chloride (55.5 g 0.25 mole) from above with 100 mls anisole (about 3.4 eq). Chill solution with ice bath while purging with N2. Slowly add 40.3 g aluminum chloride (1.2 eq 0.3 mole). Stir under N₂ for 24 hrs.

After 24 hrs, the solution was poured into 300 mls 1N HCl soln. (cold). Stir this for 15 min. Extract several times with diethyl ether. Extract organic layer once with 2% aqueous NaOH then twice with water. Dry organic layer with MgSO4, dry on vac line. Solid is washed well with ether and then ethanol before drying. Wt=34.57 g (mixture of meta, ortho and para).

Elemental theory found C 57.65 57.45 H  3.46  5.51 N 4.8 4.8 Cl 12.15 12.16

With the next step of the reduction of the ketone with trifluoromethane sulfonic aid and triethyl silane, crystallization with ethyl acetate/hexane affords pure 4-chloro-3-[4-methoxy-phenylmethyl]-nitrobenzene.

4-Chloro-3-[4-methoxy-phenylmethyl]-nitrobenzene was then reacted as specified in the synthesis of 117 and 118 from 2-chloro-4-nitrophenylmethane. From these procedures 115 and 116 can be synthesized. Compounds 111 and 113 can be synthesized from the procedure used to prepare compound 121.

Compound 114 can be prepared by reaction of 116 with ethyl mercaptan and aluminum trichloride.

Examples 85 and 86 Preparation of 117 and 118

2-Chloro-4-nitrobenzophenone is reduced with triethylsilane and trifluoromethane sulfonic acid to 2-chloro-4-nitrodiphenylmethane 32. Reaction of 32 with lithium sulfide followed by reacting the resulting sulfide with mesylate IV gives sulfide-aldehyde XXIII. Oxidation of XXIII with 2 equivalents of MCPBA yields sulfone-aldehyde XXIII. Oxidation of XXIII with 2 equivalents of MCPBA yields sulfone-aldehyde XXIV (see Scheme 5).

The sulfone-aldehyde (31.8 g) was dissolved in ethanol/toluene and placed in a parr reactor with 100 ml toluene and 100 ml of ethanol and 3.2 g of 10% Pd/C and heated to 55 C. and 100 psi of hydrogen gas for 14 hours. The reaction was then filtered to remove the catalyst. The amine product (0.076 moles, 29.5 g) from this reaction was then reacted with benzyl chloroformate (27.4 g) in toluene in the presence of 35 g of potassium carbonate and stirred at room temperature overnight. After work up by extraction with water, the CBZ protected amine product was further purified by precipitation from toluene/hexane.

The CBZ protected amine product was then reacted with 3 equivalents of potassium t-butoxide in THF at O C to yield compounds 117 and 118 which were separated by silica gel column chromatography.

Examples 89 and 90 Preparation of 121 or 122

Compound 118 (0.013 moles, 6.79 g) is dissolved in 135 ml of dry chloroform and cooled to −78 C., next 1.85 ml of boron tribromide (4.9 g) was added and the reaction is allowed to warm to room temperature. Reaction is complete after 1.5 hours. The reaction is quenched by addition of 10% potassium carbonate at 0 C. and extract with ether. Removal of ether yields compound 121. A similar procedure can be used to produce 122 from 117.

Examples 93-96

Compounds 126, 127, 128 and 129 as set forth in Table 3 were prepared substantially in the manner described above for compounds 115, 116, 111 and 113, respectively, except that fluorobenzene was used as a starting material in place of anisole.

TABLE 3 Specific Compounds (#102-111, 113-130, 132-134, 136, 138, 142-144, 262-296)

Cp# R¹ R² R³ R⁴ R⁵ R⁶ (R^(x))q 102 Et— n-Bu— HO— H— Ph— H— I⁻, 7- (CH₃)₃ N⁺— 103 n-Bu— Et— HO— H— Ph— H— I⁻, 7- (CH₃)₃N⁺— 104 Et— n-Bu— HO— H— Ph— H— 7-(CH₃)₂N— 105 Et— n-Bu— HO— H— Ph— H— 7-CH₃SO₂NH— 106 Et— n-Bu— HO— H— Ph— H— 7-Br—CH₂— CONH— 107 n-Bu— Et— HO— H— p-n- H— 7-NH₂— C₁₀H₂₁—O— Ph— 108 Et— n-Bu— HO— H— Ph— H— 7-C₅H₁₁CONH— 109 Et— n-Bu— HO— H— p-n- H— 7-NH₂— C₁₀H₂₁—O— Ph— 110 Et— n-Bu— HO— H— Ph— H— 7-CH₃CONH— 111 n-Bu— Et— HO— H— p-HO—Ph— H— 7-NH₂— 113 Et— n-Bu— HO— H— p-HO—Ph— H— 7-NH₂— 114 Et— n-Bu— HO— H— p-CH₃O—Ph— H— 7-NH₂— 115 n-Bu— Et— HO— H— p-CH₃O—Ph— H— 7-NH—CBZ 116 Et— n-Bu— HO— H— p-CH₃O—Ph— H— 7-NH—CBZ 117 n-Bu— Et— HO— H— Ph— H— 7-NH—CBZ 118 Et— n-Bu— HO— H— Ph— H— 7-NH—CBZ 119 Et— n-Bu— HO— H— Ph— H— 7-NHCO₂-t-Bu 120 n-Bu— Et— HO— H— Ph— H— 7-NHCO₂-t-Bu 121 Et— n-Bu— HO— H— Ph— H— 7-NH₂— 122 n-Bu— Et— HO— H— Ph— H— 7-NH₂— 123 Et— n-Bu— HO— H— Ph— H— 7-n-C₆H₁₃- NH— 124 n-Bu— Et— HO— H— Ph— H— 7-n-C₆H₁₃- NH— 125 Et— n-Bu— HO— H— Ph— H— I⁻, 8- (CH₃)₃)N⁺(CH₂CH₂O)₃— 126 n-Bu— Et— HO— H— p-F-Ph— H— 7-NH—CBZ 127 n-Bu— Et— HO— H— p-F-Ph— H— 7-NH₂— 128 Et— n-Bu— HO— H— p-F-Ph— H— 7-NH—CBZ 129 Et— n-Bu— HO— H— p-F-Ph— H— 7-NH₂— 130 Et— n-Bu— HO— H— Ph— H— I⁻, 8- (CH₃)₃N⁺C₆H₁₂O— 132 Et— n-Bu— HO— H— Ph— H— 8-phthalimidyl- C₆H₁₂O— 133 Et— n-Bu— HO— H— Ph— H— 8-n-C₁₀H₂₁— 134 Et— n-Bu— HO— H— Ph— H— 8-I—(C₂H₄O)₃— 136 Et— n-Bu— HO— H— Ph— H— 8-HO— 138 n-Bu— Et— HO— H— Ph— H— 8-CH₃CO₂— 142 Et— n-Bu— H— HO— H— m-CH₃O—Ph— 7-CH₃S— 143 Et— n-Bu— HO— H— m-CH₃O—Ph— H— 7-CH₃S— 144 Et— n-Bu— HO— H— p-F—Ph— H— 7-(N)-azetidine 262 Et— n-Bu— HO— H— m-CH₃O—Ph— H— 7-CH₃O— 263 Et— n-Bu— H— HO— H— m-CH₃O—Ph— 7-CH₃O— 264 Et— n-Bu— HO— H— m-CF₃—Ph— H— 7-CH₃O— 265 Et— n-Bu— H— HO— H— m-CF₃—Ph— 7-CH₃O— 266 Et— n-Bu— HO— H— m-HO—Ph— H— 7-HO— 267 Et— n-Bu— HO— H— m-HO—Ph— H— 7-CH₃O— 268 Et— n-Bu— HO— H— p-F—Ph— H— 7-CH₃O— 269 Et— n-Bu— H— HO— H— p-F—Ph— 7-CH₃O— 270 Et— n-Bu— HO— H— p-F—Ph— H— 7-HO— 271 Et— n-Bu— HO— H— m-CH₃O—Ph— H— 7-Br— 272 Et— n-Bu— H— HO— H— m-CH₃O—Ph— 7-Br— 273 Et— n-Bu— H— HO— H— p-F—Ph— 7-F— 274 Et— n-Bu— HO— H— p-F—Ph— H— 7-F— 275 Et— n-Bu— H— HO— H— m-CH₃O—Ph— 7-F— 276 Et— n-Bu— HO— H— m-CH₃O—Ph— H— 7-F— 277 Et— n-Bu— HO— H— m-F—Ph— H— 7-CH₃O— 278 Et— n-Bu— H— HO— H— o-F—Ph— 7-CH₃O— 279 Et— n-Bu— H— HO— H— m-F—Ph— 7-CH₃O— 280 Et— n-Bu— HO— H— o-F—Ph— H— 7-CH₃O— 281 Et— n-Bu— HO— H— p-F—Ph— H— 7-CH₃S— 282 Et— n-Bu— HO— H— p-F—Ph— H— 7-CH₃— 283 Et— n-Bu— H— HO— H— p-F—Ph— 7-CH₃— 284 Et— n-Bu— HO— H— p-F—Ph— H— 7-(N)-morpholine 285 Et— n-Bu— HO— H— p-F—Ph— H— 7-(N)-pyrrolidine 286 Et— Et— HO— H— Ph— H— 7-NH—CBZ— 287 Et— Et— HO— H— Ph— H— 7-NH₂— 288 CH₃— CH₃— HO— H— Ph— H— 7-NH₂— 289 n-C₃H₇— n-C₃H₇— HO— H— Ph— H— 7-NH₂— 290 n-Bu— n-Bu— HO— H— Ph— H— 7-NH₂— 291 n-Bu— n-Bu— HO— H— Ph— H— 7-NH—CBZ— 292 n-Bu— n-Bu— HO— H— p-F—Ph— H— 7-NH₂— 293 n-Bu— n-Bu— HO— H— Ph— H— 7-PhCH₂N— 294 n-Bu— n-Bu— HO— H— Ph— H— 7-(CH₃)₂N— 295 Et— n-Bu— HO— H— p-I- H— 7-NH₂— (C₂H₄O)₃—Ph— 296 Et— n-Bu— HO— H— I⁻, p- H— 7-NH₂— (CH₃)₃N⁺(C₂H₄O)₃—Ph—

TABLE 3A Bridged Benzothiepines (#101, 112, 131, 135, 137, 139-141)

CPD #101 (Example 59)

CPD #112 (Example 53)

CPD #131 (Example 56)

CPD #135 (Example 55)

CPD #137 (Example 57)

CPD #139 (Example 58)

PEG = 3400 molecular weight polyethyleneglycol bridge CPD #140 (Example 51)

CPD #141 (Example 50)

Examples 104-231

Using in each instance a method generally described in those of Examples 1 to 72 appropriate to the substituents to be introduced, including where necessary other common synthesis expedients well known to the art, compounds are prepared having the structures set forth in Table 4. The starting materials illustrated in the reaction schemes shown above are varied in accordance with principles of organic synthesis well known to the art in order to introduce the indicated substituents in the 4- and 5-positions (R³, R⁴, R⁵, R⁶) and in the indicated position on the benzo ring (R^(x)).

TABLE 4 Alternative compounds #1 (#302-312, 314-430)

Cpd# R⁵ (R^(x))q 302 p-F—Ph— 7-(1-aziridine) 303 p-F—Ph— 7-EtS— 304 p-F—Ph— 7-CH₃S(O)— 305 p-F—Ph— 7-CH₃S(O)₂— 306 p-F—Ph— 7-PhS— 307 p-F—Ph— 7-CH₃S— 9-CH₃S— 308 p-F—Ph— 7-CH₃O— 9-CH₃O— 309 p-F—Ph— 7-Et— 310 p-F—Ph— 7-iPr— 311 p-F—Ph— 7-t-Bu— 312 p-F—Ph— 7-(1-pyrazole)- 314 m-CH₃O—Ph 7-(1-azetidine) 315 m-CH₃O—Ph— 7-(1-aziridine) 316 m-CH₃O—Ph— 7-EtS—- 317 m-CH₃O—Ph— 7-CH₃S(O)— 318 m-CH₃O—Ph— 7-CH₃S(O)₂— 319 m-CH₃O—Ph— 7-PhS— 320 m-CH₃O—Ph 7-CH₃S— 9-CH₃S— 321 m-CH₃O—Ph 7-CH₃O— 9-CH₃O— 322 m-CH₃O—Ph 7-Et— 323 m-CH₃O—Ph 7-iPr— 324 m-CH₃O—Ph 7-t-Bu— 325 p-F—Ph— 6-CH₃O— 7-CH₃O— 8-CH₃O— 326 p-F—Ph— 7-(1-azetidine) 9-CH₃— 327 p-F—Ph— 7-EtS— 9-CH₃— 328 p-F—Ph— 7-CH₃S(O)— 9-CH₃— 329 p-F—Ph— 7-CH₃S(O)₂— 9-CH₃— 330 p-F—Ph— 7-PhS— 9-CH₃— 331 p-F—Ph— 7-CH₃S— 9-CH₃— 332 p-F—Ph— 7-CH₃O— 9-CH₃— 333 p-F—Ph— 7-CH₃— 9-CH₃— 334 p-F—Ph— 7-CH₃O— 9-CH₃O— 335 p-F—Ph— 7-(1-pyrrole) 336 p-F—Ph— 7-(N)N′-methylpiperazine 337 p-F—Ph— Ph— 338 p-F—Ph— 7-CH₃C(═CH₂)— 339 p-F—Ph— 7-cyclpropyl 340 p-F—Ph— 7-(CH₃)₂NHN— 341 p-F—Ph— 7-(N)-azetidine 9-CH₃S— 342 p-F—Ph— 7-(N-pyrrolidine) 9-CH₃S— 343 p-F—Ph— 7-(CH₃)₂N—- 9-CH₃S— 344 m-CH₃O—Ph— 7-(1-pyrazole) 345 m-CH₃O—Ph— 7-(N)N′-methylpiperazine 346 m-CH₃O—Ph— Ph— 347 m-CH₃O—Ph— 7-CH₃C(═CH₂)— 348 m-CH₃O—Ph— 7-cyclopropyl 349 m-CH₃O—Ph— 7-(CH₃)₂NHN— 350 m-CH₃O—Ph— 7-(N)-azetidine 9-CH₃S— 351 m-CH₃O—Ph— 7-(N-pyrrolidine)- 9-CH₃S— 352 m-CH₃O—Ph— 7-(CH₃)₂N— 9-CH₃S— 353 m-CH₃O—Ph— 6-CH₃O— 7-CH₃O— 8-CH₃O— 354 m-CH₃O—Ph— 7-(1-azetidine) 9-CH₃— 355 m-CH₃O—Ph— 7-EtS— 9-CH₃— 356 m-CH₃O—Ph— 7-CH₃S(O)— 9-CH₃— 357 m-CH₃O—Ph— 7-CH₃S(O)₂— 9-CH₃— 358 m-CH₃O—Ph— 7-PhS— 9-CH₃— 359 m-CH₃O—Ph— 7-CH₃S— 9-CH₃— 360 m-CH₃O—Ph— 7-CH₃O— 9-CH₃— 361 m-CH₃O—Ph— 7-CH₃— 9-CH₃— 362 m-CH₃O—Ph— 7-CH₃O— 9-CH₃O— 363 thien-2-yl 7-(1-aziridine) 364 thien-2-yl 7-EtS— 365 thien-2-yl 7-CH₃S(O)— 366 thien-2-yl 7-CH₃S(O)₂— 367 thien-2-yl 7-PhS— 368 thien-2-yl 7-CH₃S— 9-CH₃S— 369 thien-2-yl 7-CH₃O— 9-CH₃O— 370 thien-2-yl 7-Et— 371 thien-2-yl 7-iPr— 372 thien-2-yl 7-t-Bu— 373 thien-2-yl 7-(1-pyrrole)- 374 thien-2-yl 7-CH₃O— 375 thien-2-yl 7-CH₃S— 376 thien-2-yl 7-(1-azetidine) 377 thien-2-yl 7-Me— 378 5-Cl-thien-2-yl 7-(1-azetidine) 379 5-Cl-thien-2-yl 7-(1-aziridine) 380 5-Cl-thien-2-yl 7-EtS— 381 5-Cl-thien-2-yl 7-CH₃S(O)— 382 5-Cl-thien-2-yl 7-CH₃S(O)₂— 383 5-Cl-thien-2-yl 7-PhS— 384 5-Cl-thien-2-yl 7-CH₃S— 9-CH₃S— 385 5-Cl-thien-2-yl 7-CH₃O— 9-CH₃O— 386 5-Cl-thien-2-yl 7-Et— 387 5-Cl-thien-2-yl 7-iPr— 388 5-Cl-thien-2-yl 7-t-Bu— 389 5-Cl-thien-2-yl 7-CH₃O— 390 5-Cl-thien-2-yl 7-CH₃S— 391 5-Cl-thien-2-yl 7-Me 392 thien-2-yl 7-(1-azetidine) 9-CH₃— 393 thien-2-yl 7-EtS— 9-CH₃— 394 thien-2-yl 7-CH₃S(O)— 9-CH₃— 395 thien-2-yl 7-CH₃S(O)₂— 9-CH₃— 396 thien-2-yl 7-PhS— 9-CH₃— 397 thien-2-yl 7-CH₃S— 9-CH₃— 398 thien-2-yl 7-CH₃O— 9-CH₃— 399 thien-2-yl 7-CH₃— 9-CH₃— 400 thien-2-yl 7-CH₃O— 9-CH₃O— 401 thien-2-yl 7-(1-pyrazrole) 402 thien-2-yl 7-(N)N′-methylpiperazine 403 thien-2-yl Ph— 404 thien-2-yl 7-CH₃C(═CH₂)— 405 thien-2-yl 7-cyclpropyl 406 thien-2-yl 7-(CH₃)₂NHN— 407 thien-2-yl 7-(N)-azetidine 9-CH₃S— 408 thien-2-yl 7-(N-pyrrolidine) 9-CH₃S— 409 thien-2-yl 7-(CH₃)₂N— 9-CH₃S— 411 5-Cl-thien-2-yl 7-(1-pyrazrole) 412 5-Cl-thien-2-yl 7-(N)N′-methylpiperazine 413 5-Cl-thien-2-yl Ph— 414 5-Cl-thien-2-yl 7-CH₃C(═CH₂)— 415 5-Cl-thien-2-yl 7-cyclopropyl 416 5-Cl-thien-2-yl 7-(CH₃)₂NHN— 417 5-Cl-thien-2-yl 7-(N)-azetidine 9-CH₃S— 418 5-Cl-thien-2-yl 7-(N-pyrrolidine)- 9-CH₃S— 419 5-Cl-thien-2-yl 7-(CH₃)₂N— 9-CH₃S— 420 5-Cl-thien-2-yl 7-(1-azetidine) 9-CH₃— 421 5-Cl-thien-2-yl 7-EtS— 9-CH₃— 422 5-Cl-thien-2-yl 7-CH₃S(O)— 9-CH₃— 423 5-Cl-thien-2-yl 7-CH₃S(O)₂— 9-CH₃— 424 5-Cl-thien-2-yl 7-PhS— 9-CH₃— 425 5-Cl-thien-2-yl 7-CH₃S— 9-CH₃— 426 5-Cl-thien-2-yl 7-CH₃O— 9-CH₃— 427 5-Cl-thien-2-yl 7-CH₃— 9-CH₃— 428 5-Cl-thien-2-yl 7-CH₃O— 9-CH₃O— 429 thien-2-y1 6-CH₃O— 7-CH₃O— 8-CH₃O— 430 5-Cl-thien-2-yl 6-CH₃O— 7-CH₃O— 8-CH₃O—

Examples 232-1394

Using in each instance a method generally described in those of Examples 1 to 72 appropriate to the substituents to be introduced, including where necessary other common synthesis expedients well known to the art, compounds are prepared having the structures set forth in Table 1. The starting materials illustrated in the reaction schemes shown above are varied in accordance with principles of organic synthesis well known to the art in order to introduce the indicated substituents in the 4- and 5-positions (R³, R⁴, R⁵, R⁶) and in the indicated position on the benzo ring (R^(x)).

Example 1395 Dibutyl 4-fluorobenzene dialdehyde

Step 1: Preparation of Dibutyl 4-fluoro Benzene Dialdehyde

To a stirred solution of 17.5 g (123 mmol) of 2,5-difluorobenzaldehyde (Aldrich) in 615 mL of DMSO at ambient temperature was added 6.2 g (135 mmol) of lithium sulfide (Aldrich). The dark red solution was stirred at 75 C. for 1.5 hours, or until the starting material was completely consumed, and then 34 g (135 mmol) of dibutyl mesylate aldehyde was added at about 50 C. The reaction mixture was stirred at 75 C. for three hours or until the reaction was completed. The cooled solution was poured into water and extracted with ethyl acetate. The combined extracts were washed with water several times, dried (MgSO₄) and concentrated in vacuo. Silica gel chromatographic purification of the crude product gave 23.6 g (59%) of fluorobenzene dialdehyde as a yellow oil: ¹H NMR (CDCl₃) d 0.87 (t, J=7.05 Hz, 6H), 1.0-1.4 (m, 8H), 1.5-1.78 (m, 4H), 3.09 (s, 2H), 7.2-7.35 (m, 1H), 7.5-7.6 (m, 2H), 9.43 (s, 1H), 10.50 (d, J=2.62 Hz, 1H).

Step 2: Preparation of Dibutyl 4-fluorobenzyl Alcohol

To a solution of 22.6 g (69.8 mmol) of the dialdehyde obtained from Step 1 in 650 mL of THF at −60 C. was added 69.8 mL (69.8 mmol) of DIBAL (1M in THF) via a syringe. The reaction mixture was stirred at −40 C. for 20 hours. To the cooled solution at −40 C. was added sufficient amount of ethyl acetae to quench the excess of DIBAL, followed by 3 N HCl. The mixture was extracted with ethyl acetate, washed with water, dried (MgSO₄), and concentrated in vacuo. Silica gel chromatographic purification of the crude product gave 13.5 g (58%) of recovered starting material, and 8.1 g (36%) of the desired fluorobenzyl alcohol as a colorless oil: ¹H NMR (CDCl₃) d 0.88 (t, J=7.05 Hz, 6H), 1.0-1.4 (m, 8H), 1.5-1.72 (m, 4H), 1.94 (br s, 1H), 3.03 (s, 2H), 4.79 (s, 2H), 6.96 (dt, J=8.46, 3.02 Hz, 1H), 7.20 (dd, J=9.47, 2.82 Hz, 1H), 7.42 (dd, J=8.67, 5.64, 1H), 9.40 (s, 1H).

Step 3: Preparation of Dibutyl 4-fluorobenzyl Bromide

To a solution of 8.1 g (25 mmol) of benzyl alcohol obtained from Step 2 in 100 mL of DMF at −40 C. was added 47 g (50 mmol) of bromotriphenyphosphonium bromide (Aldrich). The resulting solution was stirred cold for 30 min, then was allowed to warm to 0 C. To the mixture was added 10% solution of sodium sulfite and ethyl acetate. The extract was washed a few times with water, dried (MgSO4), and concentrated in vacuo. The mixture was stirred in small amount of ethyl acetate/hexane mixture (1:4 ratio) and filtered through a pad of silica gel, eluting with same solvent mixture. The combined filtrate was concentrated in vacuo to give 9.5 g (98%) of the desired product as a colorless oil: ¹H NMR (CDCl₃) d 0.88 (t, J=7.05 Hz, 6H), 1.0-1.4 (m, 8H), 1.55-1.78 (m, 4H), 3.11 (s, 2H), 4.67 (s, 2H), 7.02 (dt, J=8.46, 3.02 Hz, 1H), 7.15 (dd, J=9.47, 2.82 Hz, 1H), 7.46 (dd, J=8.67, 5.64, 1H), 9.45 (s, 1H).

Step 4: Preparation of Sulfonyl 4-fluorobenzyl Bromide

To a solution of 8.5 g (25 mmol) of sulfide obtained from Step 3 in 200 mL of CH₂Cl₂ at 0° C. was added 15.9 g (60 mmol) of mCPBA (64% peracid). The resulting solution was stirred cold for 10 min, then was allowed to stirred ambient temperature for 5 hours. To the mixture was added 10% solution of sodium sulfite and ethyl acetate. The extract was washed several times with saturated Na₂CO₃, dried (MgSO₄), and concentrated in vacuo to give 10.2 g (98%) of the desired product as a colorless oil: ¹H NMR (CDCl₃) d 0.91 (t, J=7.05 Hz, 6H), 1.03-1.4 (m, 8H), 1.65-1.82 (m, 2H), 1.90-2.05 (m, 2H), 3.54 (s, 2H), 5.01 (s, 2H), 7.04-7.23 (m, 1H), 7.30 (dd, J=8.87, 2.42 Hz, 1H), 8.03 (dd, J=8.86, 5.64, 1H), 9.49 (s, 1H).

Example 1396

Generic Scheme X: The nucleophilic substitution of an appropriately substituted 2-fluorobenzaldehyde with lithium sulfide or other nucleophilic sulfide anion in polar solvent (such as DMF, DMA, DMSO .etc), followed by the addition of dialkyl mesylate aldehyde (X), provided a dialkyl benzene dialdehyde Y. DIBAL reduction of the dialdehyde at low temperature yielded benzyl alcohol monoaldehyde Z. Conversion of benzyl alcohol to benzyl bromide, followed by oxidation of sulfide to sulfone yielded the key intermediate W.

Preparation of N-propylsulfonic Acid

To a solution of 51 mg (111 μm) Compound X in ethanol (400 μl) was added 1,3 propane sultone (19.5 μl, 222 μm). The reaction was stirred in a sealed vial at 55° C. for 25 hr. Sample was concentrated under a nitrogen stream and purified by reversed phase chromatography using acetonitrile/water as eluent (30-45%) and afforded the desired material as an off-white solid (28.4 mg, 44%): ¹H NMR (CDCL₃) d 0.82-0.96 (m, 6H), 1.11-1.52 (m of m, 10H), 1.58-1.72 (m, 1H), 2.08-2.21 (m, 1H), 2.36-2.50 (m, 2H), 2.93 (s, 6H), 3.02-3.22 (m of m, 5H), 3.58-3.76 (m, 2H), 4.15 (s, 1H), 5.51 (s, 1H), 6.45-6.58 (m, 1H), 6.92-7.02 (m, 1H), 7.35-7.41 (m, 1H), 7.41-7.51 (m, 2H), 8.08 (d, J=8.1 Hz, 1H), 8.12-8.25 (m, 1H); MS ES− M−H m/z 579.

Example 1397

The 7-fluoro, 9-fluoro and 7,9-difluoro analogs of benzothiepine compounds of this invention can be reacted with sulfur and nitrogen nucleophiles to give the corresponding sulfur and nitrogen substituted analogs. The following example demonstrates the synthesis of these analogs.

3,3-Dibutyl-5a-(4′-fluorophenyl)-4a-hydroxy-7-methylthio-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide

A mixture of 0.4 g of 3,3-dibutyl-7-fluoro-5a-(4′-fluorophenyl)-4a-hydroxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide, prepared by previously described method, 0.12 g of sodium methanethiolate and 20 ml of DMF was stirred at 50 C. for 3 days. An additional 0.1 g of sodium methanethiolate was added to the reaction mixture and the mixture was stirred for additional 20 h at 50 C. then was concentrated in vacuo. The residue was triturated with water and extracte wiith ether. The ether extract was dried over MgSO₄ and concentrated in vacuo to 0.44 g of an oil. Purification by HPLC (10% EtOAc in hexane) gave 0.26 g of needles, mp 164-165.5% C.

3,3-Dibutyl-9-dimethylamino-7-fluoro-5a-(4′-fluorophenyl)-4a-hydroxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide and 7,9-Bis(dimethylamino) -3,3-dibutyl-5a-(4′-fluorophenyl)-4a-hydroxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide

A solution of 0.105 g of 3,3-dibutyl-7,9-difluoro-5a-(4′-fluorophenyl)-4a-hydroxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide, prepared by the method described previously, in 20 ml of 2 N dimethylamine in THF was heated at 160 C. in a sealed Parr reactor overnight. The reaction mixture was cooled and concentrated in vacuo. The residue was triturated with 25 ml of water and extracted with ether. The ether extract was dried over MgSO₄ and concentrated in vacuo. The resdue was purified by HPLC (10% EtOAc in hexane) to give 35 mg of an earlier fraction which was identified as 3,3-dibutyl-9-dimethylamino-7-fluoro-5a-(4′-fluorophenyl)-4a-hydroxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide, MS (CI) m/e 480 (M⁺+1), and 29 mg of a later fraction which was identified as 7,9-bis(dimethylamino)-3,3-dibutyl-5a-(4′-fluorophenyl)-4a-hydroxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide, MS (CI) m/e 505 (M⁺+1).

The compounds of this invention can also be synthesized using cyclic sulfate (XL, below) as the reagent as shown in the following schemes XI and XII. The following examples describe a procedure for using the cyclic sulfate as the reagent.

Scheme XI illustrates yet another route to benzothiepine-1,1-dioxides, particularly 3,3-dialkyl analogs, starting from the thiophenol XVIIIA. Thiophenol XVIIIA can be reacted with cyclic sulfate XL to give the alcohol XLI which can be oxidized to yield the aldehyde XLII. Aldehyde XLII itself can be further oxidized to give the sulfone XLIII which can be cyclized to give a stereoisomeric mixture of benzothiepine XLIVa and XLIVb.

Thiophenol XVIIIA can be prepared according to Scheme 3 as previously discussed and has the following formula:

wherein R⁵, R^(x) and q are as previously defined for the compounds of formula I. Cyclic sulfate XL can be prepared according to synthetic procedures known in the art and has the following formula:

wherein R¹ and R² are as previously defined for the compounds of formula I. Preferably, R¹ and R² are alkyl; more preferably, they are selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, and pentyl; and still more preferably, R¹ and R² are n-butyl.

In the process of Scheme XI, thiophenol XVIIIA is initially reacted with cyclic sulfate XL. This reaction preferably is conducted in an aprotic solvent such as methoxyethyl ether. While the reaction conditions such as temperature and time are not narrowly critical, the reaction preferably is allowed to proceed at about room temperature for about two hours. The reaction preferably employs an approximately stoichiometric ratio of the starting materials, with a slight excess of cyclic sulfate XL being preferred. Reaction time and yield can be improved by using about 1.01 to 1.3 equivalents of cyclic sulfate XL for each equivalent of thiophenol XVIIIA present. More preferably, this ratio is about 1.1 equivalents of cyclic sulfate XL for each equivalent of thiophenol XVIIIA present.

In the process of the invention, thiophenol XVIIIA also is treated with an abstracting agent. The abstracting agent can be added to the solvent containing thiophenol XVIIIA prior to, concurrently with, or after the addition of cyclic sulfate XL. Without being held to a particular theory, it is believed the abstracting agent removes the hydrogen atom from the mercaptan group attached to the benzene ring of thiophenol XVIIIA. The resulting sulfur anion of the thiophenol then reacts with cyclic sulfate XL to open the sulfate ring. The sulfur anion of the thiophenol then bonds with a terminal carbon atom of the open ring sulfate. The terminal group at the unbonded end of the open ring sulfate is the sulfate group.

The abstracting agent generally is a base having a pH greater than about 10. Preferably, the base is an alkali metal hydride such as sodium hydride, lithium hydride or potassium hydride; more preferably, the base is sodium hydride. A slight excess of abstracting agent is preferred relative to thiophenol XVIIIA. Reaction time and yield is improved by using about 1.0 to about 1.1 equivalents of abstracting agent for each equivalent of thiophenol XVIIIA present. More preferably, this ratio is about 1.1 equivalents of abstracting agent for each equivalent of thiophenol XVIIIA present.

The sulfate group of the intermediate product of the reaction of thiophenol XVIIIA with cyclic sulfate XL is then removed, preferably by hydrolysis, to yield alcohol XLI. Suitable hydrolyzing agents include mineral acids, particularly hydrochloric acid and sulfuric acid.

The several reactions involving thiophenol XVIIIA, cyclic sulfate XL, the abstracting agent and the hydrolyzing agent can take place in situ without the need for isolation of any of the intermediates produced.

Alcohol XLI is then isolated by conventional methods (for example, extraction with aqueous methyl salicylate) and oxidized using standard oxidizing agents to aldehyde XLII. Preferably, the oxidizing agent is sulfur trioxide or pyridinium chlorochromate, and more preferably, it is pyridinium chlorochromate. The reaction is conducted in a suitable organic solvent such as methylene chloride or chloroform.

Aldehyde XLII is then isolated by conventional methods and further oxidized using standard oxidizing agents to sulfone-aldehyde XLIII. Preferably, the oxidizing agent is metachloroperbenzoic acid.

Sulfone-aldehyde XLIII likewise is isolated by conventional methods and then cyclized to form the stereoisomeric benzothiepines XLIVa and XLIVb. The cyclizing agent preferably is a base having a pH between about 8 and about 9. More preferably, the base is an alkoxide base, and still more preferably, the base is potassium tert-butoxide.

The two oxidation steps of Scheme XI can be reversed without adversely affecting the overall reaction. Alcohol XLI can be oxidized first to yield a sulfone-alcohol which is then oxidized to yield a sulfone-aldehyde.

Scheme XII illustrates still another route to benzothiepine-1,1-dioxides, particularly 3,3-dialkyl analogs, starting from the halobenzene L. Halobenzene L can be reacted with cyclic sulfate XL disclosed above to give the alcohol LI which can be oxidized to yield the sulfone-alcohol LII. Sulfone-alcohol LII itself can be further oxidized to give the sulfone-aldehyde LIII which can be cyclized to give a stereoisomeric mixture of benzothiepine LIVa and LIVb.

Halobenzene L (which is commercially available or can be synthesized from commercially available halobenzenes by one skilled in the art) has the following formula:

wherein R⁵, R^(x), and q are as previously defined for the compounds of formula I; R^(h) is a halogen such as chloro, bromo, fluoro or iodo; and R^(e) is an electron withdrawing group at the ortho or para position of the halobenzene, and is preferably a p-nitro or o-nitro group. Cyclic sulfate XL can be prepared as set forth in Scheme XI and can have the following formula:

wherein R¹ and R² are as previously defined for the compounds of formula I. Preferably, R¹ and R² are alkyl; more preferably, they are selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, and pentyl; and still more preferably, R¹ and R² are n-butyl.

In the process of Scheme XII, halobenzene L is initially reacted with cyclic sulfate XL. This reaction preferably is conducted in an aprotic solvent such as dimethyl formamide or N:N-dimethylacetamide, and more preferably, in dimethyl formamide. Although the reaction conditions such as temperature and time are not narrowly critical, the reaction preferably is allowed to proceed at between about 70° C. and about 90° C. for about 8 to 12 hours. More preferably, the reaction temperature is maintained at about 80° C. The reaction preferably employs an approximately stoichiometric ratio of the starting materials, with a slight excess of cyclic sulfate XL being preferred. Reaction time and yield is improved by using about 1.1 to 1.3 equivalents of cyclic sulfate XL for each equivalent of halobenzene L present. More preferably, this ratio is about 1.1 equivalents of cyclic sulfate XL for each equivalent of halobenzene L present.

In the process of the invention, halobenzene L also is treated with an abstracting agent. The abstracting agent can be added to the solvent containing halobenzene L prior to, concurrently with, or after the addition of cyclic sulfate XL. Without being held to a particular theory, it is believed the abstracting agent removes the halogen atom attached to the benzene ring of halobenzene L and replaces that atom with a divalent sulfur atom. The resulting sulfur anion reacts with cyclic sulfate XL to open the sulfate ring. The sulfur anion of the halobenzene then bonds with a terminal carbon atom of the open ring sulfate. The terminal group at the unbonded end of the open ring sulfate is the sulfate group. The abstracting agent generally is a dialkali metal sulfide, and preferably it is dilithium sulfide. A slight excess of the abstracting agent is preferred relative to halobenzene L. Reaction time and yield is improved by using about 1.01 to 1.3 equivalents of abstracting agent for each equivalent of halobenzene L present. More preferably, this ratio is about 1.05 equivalents of abstracting agent for each equivalent of halobenzene L present.

The sulfate group of the product of the reaction of thiophenol XVIIIA with cyclic sulfate XL is then removed, preferably by hydrolysis, to yield a mixture of an ester and alcohol LI. Suitable hydrolyzing agents include mineral acids, particularly hydrochloric acid and sulfuric acid. The ester is then converted to alcohol LI by treatment with an alkali metal hydroxide, preferably sodium hydroxide.

The several reactions involving halobenzene L, cyclic sulfate XL, the abstracting agent and the hydrolyzing agent can take place in situ without the need to isolate any of the intermediates produced.

Alcohol LI is then isolated by conventional methods (for example, extraction with aqueous methyl salicylate) and oxidized using standard oxidizing agents to sulfone-alcohol LII. Preferably, the oxidizing agent is metachloroperbenzoic acid. The reaction is conducted in a suitable organic solvent such as methylene chloride or chloroform.

Sulfone-alcohol LII is then isolated by conventional methods and further oxidized using standard oxidizing agents to sulfone-aldehyde LIII. Preferably, the oxidizing agent is sulfur trioxide or pyridinium chlorochromate, and more preferably, it is pyridinium chlorochromate. The reaction is conducted in a suitable organic solvent such as methylene chloride or chloroform.

Sulfone-aldehyde XLIII is then converted to the desired benzothiepine-1,1-dioxides according to the procedure previously set forth in Scheme XI.

The two oxidation steps can be reversed without adversely affecting the overall reaction. Alcohol XLI can be oxidized first to yield an aldehyde which is then oxidized to yield a sulfone-aldehyde.

Use of the cyclic sulfate reagent instead of a mesylate reagent in Schemes XI and XII improves the overall yield and avoids many of the purification difficulties encountered relative to those reaction schemes proceeding through a mesylate intermediate. Overall yields are significantly improved when a cyclic sulfate is used instead of a mesylate reagent. In addition, chromatographic separation of the intermediate product of the cyclic sulfate coupling step of the reaction is not necessary. For example, in Schemes XI and XII the intermediate is a water soluble alkali metal salt and the impurities can be removed by extraction with ether. The intermediate is then hydrolyzed to the desired alcohol.

Example Corresponding to Scheme XI

Lithium aluminum hydride (662 ml, 1.2 equivalents, 0.66 mol) in 662 mL of 1M THF was added dropwise to a stirred solution of dibutyl-diethylmalonate (150 g, 0.55 mol) (Aldrich) in dry THF (700 ml) while maintaining the temperature of the reaction mixture at between about −20° C. to about 0° C. using an acetone/dry ice bath. The reaction mixture was then stirred at room temperature overnight. The reaction was cooled to −20° C. and 40 ml of water, 80 ml of 10% NaOH and 80 ml of water were successively added dropwise. The resulting suspension was filtered. The filtrate was dried over sodium sulphate and concentrated under vacuum to give 98.4 g (yield 95%) of the diol as an oil. Proton NMR, carbon NMR and MS confirmed the product.

A solution of the dibutyl-diol of step 1 (103 g, 0.5478 mol) in anhydrous methylene chloride (500 ml) and triethylamine (221 g, 4 equivalents, 2.19 mol) was stirred at 0° C. under nitrogen. Thionyl chloride (97.78 g, 0.82 mol) was added dropwise to the mixture. Within 5 minutes the solution turned to yellow and then to black when the addition was completed within about half an hour. The reaction was completed within 3 hours (gas chromatography confirmed no starting material was left). The mixture was washed with ice water twice, and brine twice. The organic phase was dried over magnesium sulphate and concentrated under vacuum to give 128 g (yield 100%) of the dibutyl-cyclic-sulfite as a black oil. NMR and MS were consistent with the product.

To a solution of the dibutyl-cyclic-sulfite of step 2 (127.5 g, 0.54 mol) in 600 ml acetonitrile and 500 ml of water cooled in an ice bath under nitrogen was added ruthenium(III) chloride (1 g) and sodium periodate (233 g, 1.08 mol). The reaction was stirred overnight and the color of the solution turned black. Gas chromatography confirmed there was no starting material left. The mixture was extracted once with 300 ml of ether and three times with brine. The organic phase was dried over magnesium sulphate and passed through celite. The filtrate was concentrated under vacuum and gave 133 g (yield 97.8%) of the dibutyl-cyclic-sulfate as an oil. Proton NMR, carbon NMR and MS confirmed the product.

A 60% oil dispersion of sodium hydride (0.27 g, 6.68 mmole) was washed with hexane. The hexane was decanted and 20 ml of methoxyethyl ether was added to the washed sodium hydride and cooled in an ice bath. A mixture of diphenylmethane thiophenol (1.55 g, 6.68 mmole) in 10 ml of methoxyethyl ether was added dropwise over a period of 15 minutes. A mixture of the dibutyl-cyclic-sulfate of step 3 (2.17 g, 8.66 mmole) in 10 ml of methoxyethyl ether was then added. The resulting mixture was stirred for 30 minutes at 0° C. and 1 hour at room temperature under nitrogen. Gas chromatography confirmed there was no thiol left. The solvent was evaporated and washed with water and ether two times. The water layer was separated and 20 ml of 10% NaOH was added. This aqueous mixture was boiled for 30 minutes, cooled, acidified with 6N HCI, and boiled for 10 minutes. The mixture was cooled and extracted with ether. The organic layer was washed successively with water and brine, dried over magnesium sulphate, and concentrated under vacuum to give 2.47 g (yield 92.5%) of the hexanol as an oil. Proton NMR, C13-NMR and MS confirmed the product.

To a solution of the hexanol of step 4 (2 g, 4.9 mmole) in 40 ml of methylene chloride cooled in an ice bath under nitrogen was added pyridinium chlorochromate (2.18 g, 9.9 mmole). The reaction mixture was stirred for 3 hours and filtered through silica gel. The filtrate was concentrated under vacuum to give 1.39 g (yield 70%) of the hexanal as an oil. Proton NMR, carbon NMR and MS confirmed the product.

To a solution of the hexanal of step 5 (0.44 g, 1.1 mmole) in 20 ml of methylene chloride cooled by an ice bath under nitrogen was added 70% metachloroperbenzoic acid (0.54 g, 2.2 mmole). The reaction mixture was stirred for 18 hours and filtered. The filtrate was washed successively with 10% NaOH (3×), water, and brine, dried over magnesium sulphate, and concentrated under vacuum to give 0.42 g (yield 90%) of the hexanal as an oil. Proton NMR, carbon NMR and MS confirmed the product.

A mixture of the hexanal of step 6 (0.37 g, 0.85 mmole) in 30 ml of anhydrous THF was stirred in an ice bath at a temperature of about 0° C. Potassium-tert-butoxide (102 mg, 0.85 mmole) was then added. After 3 hours thin layer chromatography confirmed the presence of the product and a small amount of the starting material. The crude reaction mixture was acidified with 10% HCl, extracted with ether, washed successively with water and brine, dried with MgSO₄, and concentrated under vacuum. This concentrate was purified by HPLC (10% EtOAc-Hexane). The first fraction came as 0.1 g of the starting material in the form of an oil. The second fraction yielded 0.27 g (75% yield) of the desired benzothiepine as a white solid. Proton NMR, carbon NMR and MS confirmed the product. (M+H=433).

Example Corresponding to Scheme XII

Chlorodiphenylmethane (10 g) was dissolved in 25 ml of DMF and lithium sulfide [1.75 g, 1.05 equivalents] was added. The solution color changed to red. The reaction mixture was heated at 80° C. overnight. The solution was cooled to 0° C. and dibutyl-cyclic-sulfate (9.9 g; prepared as set forth in Step 3 of the Scheme XI examples) in 10 ml of DMF was added and stirred at room temperature overnight. The solvent was evaporated and washed successively with water and ether (three times). The water layer was separated and 40 ml of concentrated sulfuric acid was added and the reaction mixture boiled overnight. The mixture was cooled and extracted with ethyl acetate. The organic layer was washed successively with water and brine, dried over magnesium sulphate, and concentrated under vacuum. The product was boiled with 3M of NaOH for 1 hour. The mixture was cooled and extracted with ethyl acetate. The organic layer was washed successively with water and brine, dried over magnesium sulphate, and concentrated under vacuum. The concentrate was dissolved in methylene chloride, filtered through silica gel, eluted with 20% ethyl acetate and hexane, and concentrated under vacuum to give 11.9 g (yield 74%) of the hexanol as an oil. Proton NMR, C13-NMR and MS confirmed the product.

To a solution of the hexanol of step 1 (6 g, 13 mmole) in 50 ml methylene chloride cooled in ice bath under nitrogen was added 70% MCPBA (8.261 g, 33 mmole). The reaction was stirred for 18 hours at room temperature and filtered. The filtrate was washed successively with 10% NaOH (3×), water and brine, dried over magnesium sulphate, and concentrated under vacuum. The concentrate was dissolved in methylene chloride, filtered through silica gel, eluted with 20% ethyl acetate and hexane, and concentrated under vacuum to give 5 g (yield 77.7%) of the hexanal as a white solid, MP 58-60° C. Proton NMR, C13-NMR and MS confirmed the product.

Example 1398

To a solution of 6.0 g of dibutyl 4-fluorobenzene dialdehyde of Example 1395 (14.3 mmol) in 72 mL of toluene and 54 mL of ethanol was added 4.7 g 3-nitrobenzeneboronic acid (28.6 mmol), 0.8 g of tetrakis (triphenylphosphine)palladium(O) (0.7 mmol) and 45 mL of a 2 M solution of sodium carbonate in water. This heterogeneous mixture was refluxed for three hours, then cooled to ambient temperature and partitioned between ethyl acetate and water. The organic layer was dried over MgSO₄ and concentrated in vacuo. Purification by silica gel chromatography (Waters Prep-2000) using ethyl acetate/hexanes (25/75) gave 4.8 g (73%) of the title compound as a yellow solid. ¹H NMR (CDCl₃) d 0.88 (t, J=7.45 Hz, 6H), 0.99-1.38 (m, 8H), 1.62-1.75 (m, 2H), 1.85-2.00 (m, 2H), 3.20 (s, 2H), 4.59 (s, 2H), 6.93 (dd, J=10.5 and 2.4 Hz, 1H), 7.15 (dt, J=8.4 and 2.85 Hz, 1H), 7.46-7.59 (m, 2H), 8.05-8.16 (m, 3H), 9.40 (s, 1H).

A solution of 4.8 g (10.4 mmol) of 2 in 500 mL THF was cooled to 0° C. in an ice bath. 20 mL of a 1 M solution of potassium t-butoxide was added slowly, maintaining the temperature at <5° C. Stirring was continued for 30 minutes, then the reaction was quenched with 100 mL of saturated ammonium chloride. The mixture was partitioned between ethyl acetate and water; the organic layer was washed with brine, then dried (MgSO₄) and concentrated in vacuo. Purification by silica gel chromatography through a 100 ml plug using CH₂Cl₂ as eluent yielded 4.3 g (90%) of 3 as a pale yellow foam. ¹H NMR (CDCl₃) d 0.93 (t, J=7.25 Hz, 6H), 1.00-1.55 (m, 8H), 1.59-1.74 (m, 3H), 2.15-2.95 (m, 1H), 3.16 (q_(AB), J_(AB)=15.0 Hz, ΔV=33.2 Hz, 2H), 4.17 (d, J=6.0 Hz, 1H), 5.67 (s, 1H), 6.34 (dd, J=9.6 and 3.0 Hz, 1H), 7.08 (dt, J=8.5 and 2.9 Hz, 1H), 7.64 (t, J=8.1 Hz, 1H), 7.81 (d, J=8.7 Hz, 1H), 8.13 (dd, J=9.9 and 3.6 Hz, 1H), 8.23-8.30 (m, 1H), 8.44 (s, 1H). MS (FABH⁺) m/e (relative intensity) 464.5 (100), 446.6 (65). HRMS calculated for M+H 464.1907. Found 464.1905.

To a cooled (0° C.) solution of 4.3 g (9.3 mmol) of 3 in 30 ml THF contained in a stainless steel reaction vessel was added 8.2 g dimethyl amine (182 mmol). The vessel was sealed and heated to 110° C. for 16 hours. The reaction vessel was cooled to ambient temperature and the contents concentrated in vacuo. Purification by silica gel chromatography (Waters Prep-2000) using an ethyl acetate/hexanes gradient (10-40% ethyl acetate) gave 4.0 g (88%) of 4 as a yellow solid. ¹H NMR (CDCl₃) d 0.80-0.95 (m, 6H), 0.96-1.53 (m, 8H), 1.60-1.69 (m, 3H), 2.11-2.28 (m, 1H), 2.79 (s, 6H), 3.09 (q_(AB), J_(AB)=15.0 Hz, DV=45.6 Hz, 2H), 4.90 (d, J=9.0 Hz, 1H), 5.65 (s, 1H), 5.75 (d, J=2.1 Hz, 1H), 6.52 (dd, J=9.6 and 2.7 Hz, 1H), 7.59 (t, J=8.4 Hz, 1H), 7.85 (d, J=7.80 Hz, 1H), 7.89 (d, J=9.0 Hz, 1H), 8.20 (dd, J=8.4 and 1.2 Hz, 1H), 8.43 (s, 1H). MS (FABH⁺) m/e (relative intensity) 489.6 (100), 471.5 (25). HRMS calculated for M+H 489.2423. Found 489.2456.

To a suspension of 1.0 g (2.1 mmol) of 4 in 100 ml ethanol in a stainless steel Parr reactor was added 1 g 10% palladium on carbon. The reaction vessel was sealed, purged twice with H₂, then charged with H₂ (100 psi) and heated to 45° C. for six hours. The reaction vessel was cooled to ambient temperature and the contents filtered to remove the catalyst. The filtrate was concentrated in vacuo to give 0.9 g (96%) of 5. ¹H NMR (CDCl₃) d 0.80-0.98 (m, 6H), 1.00-1.52 (m, 10H), 1.52-1.69 (m, 1H), 2.15-2.29 (m, 1H), 2.83 (s, 6H), 3.07 (q_(AB), J_(AB)=15.1 Hz, DV=44.2 Hz, 2H), 3.70 (s, 2H), 4.14 (s, 1H), 5.43 (s, 1H), 6.09 (d, J=2.4 Hz, 1H), 6.52 (dd, J=12.2 and 2.6 Hz, 1H), 6.65 (dd, J=7.8 and 1.8 Hz, 1H), 6.83 (s, 1H), 6.93 (d, J=7.50 Hz, 1H), 7.19 (t, J=7.6 Hz, 1H), 7.89 (d, J=8.9 Hz, 1H). MS (FABH⁺) m/e (relative intensity) 459.7 (100). HRMS calculated for M+H 459.2681. Found 459.2670.

Step 6. Preparation of 6

To a solution of 914 mg (2.0 mmol) of 5 in 50 ml THF was added 800 mg (4.0 mmol) 5-bromovaleroyl chloride. Next was added 4 g (39.6 mmol) TEA. The reaction was stirred 10 minutes, then partitioned between ethyl acetate and brine. The organic layer was dried (MgSO₄) and concentrated in vacuo. Purification by silica gel chromatography through a 70 ml MPLC column using a gradient of ethyl acetate(20-50%) in hexane as eluent yielded 0.9 g (73%) of 6 as a pale yellow oil. ¹H NMR (CDCl₃) d 0.84-0.95 (m, 6H), 1.02-1.53 (m, 10H), 1.53-1.68 (m, 1H), 1.80-2.00 (m, 4H), 2.12-2.26 (m, 4H), 2.38 (t, J=6.9 Hz, 2H), 2.80 (s, 6H), 3.07 (q_(AB), J_(AB)=15.6 Hz, DV=40.4 Hz, 2H), 3.43 (t, J=6.9 Hz, 2H), 4.10 (s, 1H), 5.51 (s, 1H), 5.95 (d, J=2.4 Hz, 1H), 6.51 (dd, J=9.3 and 2.7 Hz, 1H), 7.28 (s, 1H), 7.32-7.41 (m, 2H), 7.78 (d, J=8.1 Hz, 1H), 7.90 (d, J=9.0 Hz, 1H).

To a solution of 0.9 g (1.45 mmol) of 6 in 25 ml acetonitrile add 18 g (178 mmol) TEA. Heat at 55° C. for 16 hours. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. Purification by reverse-phase silica gel chromatography (Waters Delta Prep 3000) using an acetonitrile/water gradient containing 0.05% TFA (20-65% acetonitrile) gave 0.8 g (73%) of 7 as a white foam. ¹H NMR (CDCl₃) d 0.80-0.96 (m, 6H), 0.99-1.54 (m, 19H), 1.59-1.84 (m, 3H), 2.09-2.24 (m, 1H), 2.45-2.58 (m, 2H), 2.81 (s, 6H), 3.09 (q_(AB), J_(AB)=15.6 Hz, DV=18.5 Hz, 2H), 3.13-3.31 (m, 8H), 4.16 (s, 1H), 5.44 (s, 1H), 6.08 (d, J=1.8 Hz, 1H), 6.57 (dd, J=9.3 and 2.7 Hz, 1H), 7.24 (t, J=7.5 Hz, 1H), 7.34 (t, J=8.4 Hz, 1H), 7.56 (d, J=8.4 Hz, 1H), 7.74 (s, 1H), 7.88 (d, J=9.0 Hz, 1H), 9.22 (s, 1H). HRMS calcd 642.4304; observed 642.4343.

Example 1398a

In an inert atmosphere, weigh out 68.3 gms phosphorus pentachloride (0.328 mole Aldrich 15,777-5) into a 2-necked 500 ml round bottom flask. Fit flask with a N₂ inlet adapter and suba seal. Remove from inert atmosphere and begin N₂ purge. Add 50 mls anhydrous chlorobenzene (Aldrich 28,451-3) to the PCl₅ via syringe and begin stirring with magnetic stir bar.

Weigh out 60 gms 2-chloro-5-nitrobenzoic acid (0.298 mole Aldrich 12,511-3). Slowly add to the chlorobenzene solution while under N₂ purge. Stir at room temperature overnight. After stirring at room temperature for ˜20 hrs, place in oil bath and heat at 50 C. for 1 hr. Remove chlorobenzene by high vacuum. Wash residue with anhydrous hexane. Dry acid chloride wt=61.95 gms. Store in inert and dry atmosphere.

In inert atmosphere, dissolve acid chloride with 105 mls anhydrous anisole (0.97 mole Aldrich 29,629-5). Place solution in a 2-necked 500ml round bottom flask.

Weigh out 45.1 gms aluminum chloride (0.34 moles Aldrich 29,471-3) and place in a solid addition funnel. Fit reaction flask with addition funnel and a N₂ inlet adapter. Remove from inert atmosphere. Chill reaction solution with ice bath and begin N₂ purge. Slowly add AlCl₃ to chilled solution. After addition is complete, allow to warm to room temperature. Stir overnight.

Quench reaction by pouring into a solution of 300 mls 1N HCl and ice. Stir 15 min. Extract twice with ether. Combine organic layers and extract twice with 2% NaOH, then twice with deionized H₂O. Dry with MgSO₄, filter and rotovap to dryness. Remove anisole by high vacuum. Crystalize product from 90% ethanol 10% ethyl acetate. Dry on vacuum line. Wt=35.2 gms. Yield 41%. Obtain NMR and mass spec (m/z=292).

Dissolve 38.10 gms (0.131 moles) of the benzophenone from step 1 in 250 mls anhydrous methylene chloride. Place in a 3 liter flask fitted with N₂ inlet, addition funnel and stopper. Stir with magnetic stir bar. Chill solution with ice bath.

Prepare a solution of 39.32 gms trifluoromethane sulfonic acid (0.262 mole Aldrich 15,853-4) and 170 mls anhydrous methylene chloride. Place in addition funnel and add dropwise to chilled solution under N₂. Stir 5 minutes after addition is complete.

Prepare a solution of 22.85 g ms triethyl silane (0.197 mole Aldrich 23,019-7) and 170 mls anhydrous methylene chloride. Place in addition funnel and add dropwise to chilled solution under N₂. Stir 5 minutes after addition is complete.

Prepare a second solution of 39.32 gms trifluoromethane sulfonic acid and 170 mls anhydrous methylene chloride. Place in addition funnel and add dropwise to chilled solution under N₂. Stir 5 minutes after addition is complete.

Prepare a second solution of 22.85 gms triethyl silane and 170 mls anhydrous methylene chloride. Place in addition funnel and add dropwise to chilled solution under N₂. After all additions are made allow to slowly warm to room temperature overnight. Stir under N₂ overnight.

Prepare 1300 mls saturated NaHCO₃ in a 4 liter beaker. Chill with ice bath. While stirring vigorously, slowly add reaction mixture. Stir at chilled temperature for 30 min. Pour into a separatory funnel and allow separation. Remove organic layer and extract aqueous layer 2 times with methylene chloride. Dry organic layers with MgSO₄. Crystallize from ethanol. Dry on vacuum line. Dry wt=28.8 gms. Confirm by NMR and mass spec (m/z=278).

Dissolve 10.12 gms (0.036 moles) of product 2 with 200 mls anhydrous DMSO. Place in a 500 ml round bottom flask with magnetic stir bar. Fit flask with water condenser, N₂ inlet, and stopper. Add 1.84 gms Li₂S (0.040 moles Aldrich 21,324-1). Place flask in oil bath and heat at 75° C. under N₂ overnight then cool to room temperature.

Weigh out 10.59 gms dibutyl mesylate (0.040 moles). Dissolve with anhydrous DMSO and add to reaction solution. Purge well with N₂, heat overnight at 80° C.

Cool to room temperature. Prepare 500 mls of 5% acetic acid in a 2 liter beaker. While stirring, slowly add reaction mixture. Stir 30 min. Extract with ether 3 times. Combine organic layers and extract with water and sat'd NaCl. Dry organic layer with MgSO₄, filter and rotovap to dryness. Dry oil on vacuum line. Obtain pure product by column chromatography using 95% hexane and 5% ethyl acetate as the mobile phase. Dry wt=7.8 gms. Obtain NMR and mass spec (m/z=444).

Dissolve 9.33 gms (0.021 moles) of product 3 with 120 mls anhydrous methylene chloride. Place in a 250 ml round bottom flask with magnetic stir bar. Fit flask with N₂ inlet and stopper. Chill solution with ice bath under N₂ purge. Slowly add 11.54 gms 3-chloroperbenzoic acid (0.0435 moles, Fluka 25800, ˜65%). After addition is complete warm to room temperature and monitor reaction by TLC. Reaction goes quickly to the sulphoxide intermediate but takes 8 hrs to convert to the sulphone. Chill solution over night in freezer. Filter solid from reaction, extract filtrate with 10% K₂CO₃. Extract aqueous layer twice with methylene choride. Combine organic layers and dry with MgSO₄. Filter and rotovap to dryness. Obtain pure product by crystallizing from ethanol or isolating by column chromatography. Obtain NMR and mass spec (m/z=476).

Reaction is done in a 300 ml stainless steel Parr stirred mini reactor. Place 9.68 gms (0.0204 moles) of product 4 in reactor base. Add 160 mls ethanol. For safety reasons next two compounds are added in a N₂ atmosphere glove bag. In glove bag, add 15.3 mls formaldehyde (0.204 moles, Aldrich 25,254-9, about 37 wt % in water) and 1.45 gms 10% Pd/Carbon (Aldrich 20,569-9). Seal reactor before removing from glove bag. Purge reactor three times with H₂. Heat to 55° C. under H₂. Run reaction at 200 psig H₂, 55° C., and a stir rate of 250 rpm. Run overnight under these conditions.

Cool reactor and vent H₂. Purge with N₂. Check progress of run by TLC. Reaction is a mixture of desired product and intermediate. Filter reaction mixture over a bed of celite washing well with ether. Rotovap and redissolve with ether. Extract with water. Dry organic layer with MgSO₄, filter and rotovap to dryness. Dry on vacuum line.

Charge reactor again with same amounts, seal reactor and run overnight under same conditions. After second run all of the material has been converted to the desired product. Cool and vent H₂ pressure. Purge with N₂. Filter over a bed of celite, washing well with ether. Rotovap to dryness. Dissolve with ether and extract with water. Dry organic layer with MgSO₄, filter and rotovap to dryness. Dry on vacuum line. Obtain NMR and mass spec (m/z=474).

Dissolve 8.97 gms (0.0189 mole) of product 5 with 135 mls anhydrous THF. Place in a 250 ml round bottom flask with magnetic stir bar. Fit flask with N₂ inlet and stopper. Chill solution with ice/salt bath under N₂ purge. Slowly add 2.55 gms potassium t-butoxide (0.227 mole Aldrich 15,667-1). After addition is complete, continue to stir at −10° C. monitoring by TLC. Once reaction is complete, quench by adding 135 mls 10% HCl stirring 10 min. Extract three times with ether. Dry organic layer with MgSO₄, filter and rotovap to dryness. Crystallize from ether. Obtain NMR and mass spec (m/z=474).

Dissolve 4.67 gms (0.01 moles) of product 6 with 100 mls anhydrous chloroform. Place in a 250 ml round bottom flask with magnetic stir bar. Fit flask with N₂ inlet adapter and suba seal. Chill solution with dry ice/acetone bath under a N₂ purge. Slowly add, via syringe, 2.84 mls boron tribromide (0.03 moles Aldrich 20,220-7). Stir at cold temperature for 15 min after addition then allow to warm to room temperature. Monitor reaction progress by TLC. Reaction is usually complete in 3 hrs.

Chill solution with ice bath. Quench with 100 mls 10% K₂CO₃ while stirring rapidly. Stir 10 min. then transfer to sep funnel and allow separation. Remove aqueous layer. Extract organic layer once with 10% HCl, once H₂O, and once with saturated NaCl solution. Dry organic layer with MgSO₄, filter and rotovap to dryness. Crystallize product from ether. Obtain NMR and mass spec (m/z=460).

Weigh 0.38 gms NaH (9.57 mmoles Aldrich 19,923-0 60% disp. in mineral oil) in a 250 ml round bottom flask with magnetic stir bar. Fit flask with N₂ inlet and stopper. Chill NaH with ice bath and begin N₂ purge.

Dissolve 4.0 gms (8.7 mmoles) of product 7 with 60 mls anhydrous DMF. Add to the cold NaH. Stir at cold temperature for 30 min. Add 1.33 gms K₂CO₃ (9.57 mmoles Fisher P-208).

Dissolve 16.1 gms 1,2-bis-(2-iodoethoxy)ethane (43.5 mmoles Aldrich 33,343-3) with 60 mls anhydrous DMF. Add to cold reaction mixture. Warm to room temperature then heat to 40° C. overnight under N₂.

Cleanup by diluting with ether and extracting sequentially with 5% NaOH, H₂O, and saturated NaCl. Dry organic layer with MgSO₄, filter and dry. Obtain pure product by column chromatography using 75% hexane 25% ethyl acetate as the mobile phase. Obtain NMR and mass spec (m/z=702).

Dissolve 1.0 gms (1.43 mmoles) of product 8 with 10 mls anhydrous acetonitrile. Place in a 3 ounce Fischer-Porter pressure reaction vessel with magnetic stir bar. Add 2.9 gms triethyl amine (28.6 mmoles Aldrich 23,962-3) dissolved in 10 mls anhydrous acetonitrile. Purge well with N₂ then close system Heat at 45° C. Monitor reaction by TLC. Reaction is usually complete in 48 hrs.

Perform cleanup by removing acetonitrile under vacuum. Redissolve with anhydrous chloroform and precipitate quaternary ammonium salt with ether. Repeat several times. Dry to obtain crystalline product. Obtain NMR and mass spec (m/z=675).

Example 1399

To a solution of 144 g of KOH (2560 mmol) in 1.1 L of DMSO was added 120 g of 2-bromobenzyl alcohol (641 mmol) slowly via addition funnel. Then was added 182 g of methyliodide (80 mL, 1282 mmol) via addition funnel. Stirred at ambient temperature for fifteen minutes. Poured reaction contents into 1.0 L of water and extracted three times with ethyl acetate. The organic layer was dried over MgSO₄ and concentrated in vacuo. Purified by silica-gel chromatography through a 200 mL plug using hexanes (100%) as elutant yielded 103.2 g (80%) of 1 as a clear colorless liquid. ¹H NMR (CDCl₃) d 3.39 (s, 3H), 4.42 (s, 2H), 7.18-7.27 (m, 2H), 7.12 (d, J=7.45, 1H), 7.50 (s, 1H).

To a cooled (−78° C.) solution of 95 g (472 mmol) of 1 in 1.5 L THF was added 240 mL of 2.5 M n-butyl lithium (576 mmol). The mixture was stirred for one hour, and then to it was added 180 g of zinc iodide (566 mmol) dissolved in 500 ml THF. The mixture was stirred thirty minutes, allowed to warm to 5 C., cooled to −10° C. and to it was added 6 g of Pd(PPh₃)₄ (5.2 mmol) and 125 g 2,5-difluorobenzoyl chloride (708 mmol). The mixture was stirred at ambient temperature for 18 hoursand then cooled to 10° C., quenched with water, partitioned between ethyl acetate and water, and washed organic layer with 1N HCL and with 1N NaOH. The organic layer was dried over MgSO₄ and concentrated in vacuo. Purification by silica gel chromatography (Waters Prep-500) using 5% ethyl acetate/hexanes as elutant gave 53.6 g (43%) of 2 as an orange oil. ¹H NMR (CDCl₃) d 3.40 (s, 3H), 4.51 (s, 2H), 7.12-7.26 (m, 3H), 7.47 (t, J=7.50, 1H), 7.57 (d, J=7.45, 1H), 7.73 (d, J=7.45, 1H), 7.80 (s, 1H).

A solution of 53 g (202.3 mmol) of 2 and 11.2 g Li2S (242.8 mmol) in 250 mL DMF was heated to 100° C. for 18 hours. The reaction was cooled (0° C.) and 60.7 g of X′ (the cyclic sulfate compound of example 1397) (242.8 mmol) in 50 mL DMF was added. Stirred at ambient temperature for 18 hours then condensed in vacuo. Added 1 L water to organic residue and extracted twice with diethyl ether. Aqueous layer acidified (pH 1) and refluxed 2 days. Cooled to ambient temperature and extracted with methylene chloride, dried organic layer over MgSO₄ and condensed in vacuo. Purification by silica gel chromatography (Waters Prep-500) using 10% ethyl acetate/hexanes as elutant gave 42.9 g (48%) of 3 as a yellow oil. ¹H NMR (CDCl₃) d 0.86 (t, J=7.25 Hz, 6H), 1.10-1.26 (m, 12H), 2.83 (s, 2H), 3.32 (s, 2H), 3.40 (s, 3H), 4.48 (s, 3H), 7.02 (dd, J=8.26 Hz and 2.82 Hz, 1H), 7.16 (dt, J=8.19 Hz and 2.82 Hz, 1H), 7.45 (t, J=7.65 Hz, 1H), 7.56-7.61 (m, 2H), 7.69 (d, J=7.85 Hz, 1H), 7.74 (s, 1H).

To a cooled (−40° C.) solution of 42.9 g (96.2 mmol) of 3 in 200 mL of methylene chloride was added 21.6 g trifluoromethane sulfonic acid (12.8 mL, 144 mmol), followed by the addition of 22.4 g triethyl silane (30.7 mL, 192.4 mmol). Stirred at −20° C. for two hours, quenched with water and warmed to ambient temperature. Partitioned between methylene chloride and water, dried the organic layer over MgSO₄ and condensed in vacuo. Purification by silica gel chromatography (Waters Prep-500) using 10% ethyl acetate/hexanes as elutant gave 24.2 g (60%) of 4 as a oil. ¹H NMR (CDCl₃) d 0.89 (t, J=7.05 Hz, 6H), 1.17-1.40 (m, 12H), 1.46 (t, J=5.84 Hz, 1H), 2.81 (s, 2H), 3.38 (s, 3H), 3.43 (d, J=5.23 Hz, 2H), 4.16 (s, 2H), 4.42 (s, 2H), 6.80 (d, J=9.67 Hz, 1H), 6.90 (t, J=8.46 Hz, 1H), 7.09 (d, J=7.45 Hz, 1H), 7.15-7.21 (m, 2H), 7.25-7.32 (m, 2H), 7.42 (m, 1H)

To a cooled (15-18° C.) solution of 24.2 g (55.8 mmol) of 4 in 100 mL DMSO was added 31.2 g sulfur trioxide pyridine complex (195 mmol). Stirred at ambient temperature for thirty minutes. Poured into cold water and extracted three times with ethyl acetate. Washed organics with 5% HCl (300 mL) and then with brine (300 mL), dired organics over MgSO₄ and condensed in vacuo to give 23.1 g (96%) of 5 as a light brown oil. ¹H NMR (CDCl₃) d 0.87 (t, J=7.05 Hz, 6H), 1.01-1.32 (m, 8H), 1.53-1.65 (m, 4H), 2.98 (s, 2H), 3.38 (s, 3H), 4.15 (s, 2H), 4.43 (s, 2H), 6.81 (dd, J=9.66 Hz and 2.82 Hz, 1H), 6.91 (t, J=8.62 Hz, 1H), 7.07 (d, J=7.46 Hz, 1H), 7.14 (s, 1H), 7.19 (d, J=7.65 Hz, 1H), 7.26-7.32 (m, 1H), 7.42 (dd, J=8.66 Hz and 5.64 Hz, 1H), 9.40 (s, 1H).

To a cooled (0° C.) solution of 23.1 g (53.6 mmol) of 5 in 200 mL methylene chloride was added 28.6 g meta cholorperoxy-benzoic acid (112.6 mmol). Stirred at ambient temperature for 24 hours. Quenched with 100 mL 10% Na₂SO₃, partitioned between water and methylene chloride. Dried organic layer over MgSO₄ and condensed in vacuo to give 24.5 g (98%) of 6 as a light yellow oil. ¹H NMR (CDCl₃) d 0.86-1.29 (m, 14H), 1.58-1.63 (m, 2H), 1.82-1.91 (m, 2H), 3.13 (s, 2H), 3.39 (s, 3H), 4.44 (s, 2H), 4.50 (s, 2H), 6.93 (d, J=9.07 Hz, 1H), 7.10-7.33 (m, 5H), 8.05 (s, 1H), 9.38 (s, 1H).

To a solution of 24.5 g (52.9 mmol) of 6 in 20 mL of THF contained in a stainless steel reaction vessel was added 100 mL of a 2.0 M solution of dimethyl amine and 20 mL of neat dimethyl amine. The vessel was sealed and heated to 110° C. for 16 hours. The reaction vessel was cooled to ambient temperature and the contents concentrated in vacuo. Purification by silica gel chromatography (Waters Prep-500) using 15% ethyl acetate/hexanes gave 21.8 g (84%) of 7 as a clear colorless oil. ¹H NMR (CDCl₃) d 0.85 (t, J=7.25 Hz, 6H), 0.93-1.29 (m, 8H), 1.49-1.59 (m, 2H), 1.70-1.80 (m, 2H), 2.98 (s, 8H), 3.37 (s, 3H), 4.41 (s, 2H), 4.44 (s, 2H), 6.42 (s, 1H), 6.58 (dd, J=9.0 Hz and 2.61 Hz, 1H), 7.13 (d, J=7.45 Hz, 1H), 7.21 (s, 1H), 7.28 (t, J=7.85 Hz, 1H), 7.82 (d, J=9.06 Hz, 1H), 9.36 (s, 1H).

A solution of 21.8 g (44.8 mmol) of 7 in 600 mL of THF was cooled to 0° C. 58.2 mL of a 1 M solution of potassium t-butoxide was added slowly, maintaining the temperature at <5° C. Stirred for 30 minutes, then quenched with 50 mL of saturated ammonium chloride. The organic layer was partitioned between ethyl acetate and water, dried over MgSO4 and concentrated in vacuo. Purification by recrystalization from ˜10% ethyl acetate/hexanes gave 15.1 g of 8 as a white solid. The mother liquor was purified by silica gel chromatography (Waters Prep-500) using 30% ethyl acetate/hexanes as the elutant to give 3.0 g of 8 as a white solid. MS (FABLi⁺) m/e 494.6. HRMS (EI⁺) calculated for M+H 487.2756. Found 487.2746.

A solution of 2.0 g (4.1 mmol) of 8 in 20 mL of methylene chloride was cooled to −60° C. 4.1 mL of a 1M solution of boron tribromide was added. Stirred at ambient temperature for thirty minutes. Cooled reaction to ˜10° C. and quenched with 50 mL of water. The organic layer was partitioned between methylene chloride and water, dried over MgSO₄ and concentrated in vacuo. Purification by recrystalization from 50% ethyl acetate/methylene chloride gave 1.95 g (89%) of 9 as a white solid. MS (FABH⁺) m/e 537. HRMS (FAB) calculated for M 536.1834. Found 536.1822.

A solution of 1.09 g (2.0 mmol) of 9 and 4.9 g (62 mmol) of pyridine in 30 mL of acetonitrile was stirred at ambient temperature for 18 hours. The reaction was concentrated in vacuo. Purification by recrystallization from methanol/diethyl ether gave 1.19 g (96%) of 10 as an off white solid. MS (FAB⁺) m/e 535.5.

Example 1400

A 12-liter, 4-neck round-bottom flask was equipped with reflux condenser, N₂ gas adaptor, mechanical stirrer, and an addition funnel. The system was purged with N₂. A slurry of sodium hydride (126.0 g/4.988 mol) in toluene (2.5 L) was added, and the mixture was cooled to 6 C. A solution of 4-fluorophenol (560.5 g/5.000 mol) in toluene (2.5 L) was added via addition funnel over a period of 2.5 h. The reaction mixture was heated to reflux (100 C.) for 1 h. A solution of 3-methoxybenzyl chloride (783.0 g/5.000 mol) in toluene (750 mL) was added via addition funnel while maintaining reflux. After 15 h. refluxing, the mixture was cooled to room temperature and poured into H₂O (2.5 L). After 20 min. stirring, the layers were separated, and the organic layer was extracted with a solution of potassium hydroxide (720 g) in MeOH (2.5 L). The MeOH layer was added to 20% aqueous potassium hydroxide, and the mixture was stirred for 30 min. The mixture was then washed 5 times with toluene. The toluene washes were extracted with 20% aq. KOH. All 20% aq. KOH solutions were combined and acidified with concentrated HCl. The acidic solution was extracted three times with ethyl ether, dried (MgSO₄), filtered and concentrated in vacuo. The crude product was purified by Kugelrohr distillation to give a clear, colorless oil (449.0 g/39% yield). b.p.: 120-130 C./50mtorrHg. ¹H NMR and MS [(M+H)⁺=233] confirmed desired structure.

A 12-liter, 3-neck round-bottom flask was fitted with mechanical stirrer and N₂ gas adaptor. The system was purged with N₂. 4-Fluoro-2-(3-methoxybenzyl)-phenol (455.5 g/1.961 mol) and dimethylformamide were added. The solution was cooled to 6 C., and sodium hydride (55.5 g/2.197 mol) was added slowly. After warming to room temperature, dimethylthiocarbamoyl chloride (242.4 g/1.961 mol) was added. After 15 h, the reaction mixture was poured into H₂O (4.0 L), and extracted two times with ethyl ether. The combined organic layers were washed with H₂O and saturated aqueous NaCl, dried (MgSO₄), filtered, and concentrated in vacuo to give the product (605.3 g, 97% yield). ¹H NMR and MS [(M+H)⁺=320] confirm desired structure.

A 12-liter, round-bottom flask was equipped with N₂ gas adaptor, mechanical stirrer, and reflux condenser. The system was purged with N₂. 4-Fluoro-2-(3-methoxybenzyl)-phenyldimethylthiocarbamate (605.3 g/1.895 mol) and phenyl ether (2.0 kg) were added, and the solution was heated to reflux for 2 h. The mixture was stirred for 64 h. at room temparature and then heated to reflux for 2 h. After cooling to room temperature, MeOH (2.0 L) and THF (2.0 L) were added, and the solution was stirred for 15 h. Potassium hydroxide (425.9 g/7.590 mol) was added, and the mixture was heated to reflux for 4 h. After cooling to room temparature, the mixture was concentrated by rotavap, dissolved in ethyl ether (1.0 L), and extracted with H₂O. The aqueous extracts were combined, acidified with concentrated HCl, and extracted with ethyl ether. The ether extracts were dried (MgSO₄), filtered, and concentrated in vacuo to give an amber oil (463.0 g, 98% yield). ¹H NMR confirmed desired structure.

A 5-liter, 3-neck, round-bottom flask was equipped with N₂ gas adaptor and mechanical stirrer. The system was purged with N₂. 4-Fluoro-2-(3-methoxybenzyl)-thiophenol (100.0 g/403.2 mmol) and 2-methoxyethyl ether (1.0 L) were added and the solution was cooled to 0C. Sodium hydride (9.68 g/383.2 mmol) was added slowly, and the mixture was allowed to warm to room temparature, 2,2-Dibutylpropylene sulfate (110.89 g/443.6 mmol) was added, and the mixture was stirred for 64 h. The reaction mixture was concentrated by rotavap and dissolved in H₂O. The aqueous solution was washed with ethyl ether, and concentrated H₂SO₄ was added. The aqueous solution was heated to reflux for 30 min, cooled to room temperature, and extracted with ethyl ether. The ether solution was dried (MgSO₄), filtered, and conc'd in vacuo to give an amber oil (143.94 g/85% yield). ¹H NMR and MS [(M+H)⁺=419] confirm the desired structure.

A 2-liter, 4-neck, round-bottom flask was equipped with N₂ gas adaptor, and mechanical stirrer. The system was purged with N₂. The corresponding alcohol (143.94 g/343.8 mmol) and CH₂Cl₂ (1.0 L) were added and cooled to 0 C. Pyridinium chlorochromate (140.53 g/651.6 mmol) was added. After 6 h., CH₂Cl₂ was added. After 20 min, the mixture was filtered through silica gel, washing with CH₂Cl₂. The filtrate was concentrated in vacuo to give a dark yellow-red oil (110.6 g, 77% yield). ¹H NMR and MS [(M+H)⁺=417] confirm the desired structure.

A 2-liter, 4-neck, round-bottom flask was equipped with N₂ gas adaptor and mechanical stirrer. The system was purged with N₂. The corresponding sulfide (110.6 g/265.5 mmol) and CH₂Cl₂ (1.0 L) were added. The solution was cooled to 0 C., and 3-chloroperbenzoic acid (158.21 g/531.7 mmol) was added portionwise. After 30 min, the reaction mixture was allowed to warm to room temperature After 3.5 h, the reaction mixture was cooled to 0 C. and filtered through a fine fritted funnel. The filtrate was washed with 10% aqueous K₂CO₃. An emulsion formed which was extracted with ethyl ether. The organic layers were combined, dried (MgSO₄), filtered, and concentrated in vacuo to give the product (93.2 g, 78% yield). ¹H NMR confirmed the desired structure.

A 2-liter, 4-neck, round-bottom flask was equipped with N₂ gas adaptor, mechanical stirrer, and a powder addition funnel. The system was purged with N₂. The corresponding aldehyde (93.2 g/208 mmol) and THF (1.0 L) were added, and the mixture was cooled to 0 C. Potassium tert-butoxide (23.35 g/208.1 mmol) was added via addition funnel. After 1 h, 10% aq/HCl (1.0 L) was added. After 1 h, the mixture was extracted three times with ethyl ether, dried (MgSO₄), filtered, and concentrated in vacuo. The crude product was purified by recryst. from 80/20 hexane/ethyl acetate to give a white solid (32.18 g). The mother liquor was concentrated in vacuo and recrystelized from 95/5 toluene/ethyl acetate to give a white solid (33.60g/combined yield: 71%). ¹H NMR confirmed the desired product.

A Fisher porter bottle was fitted with N₂ line and magnetic stirrer. The system was purged with N₂. The corresponding fluoro-compound (28.1 g/62.6 mmol) was added, and the vessel was sealed and cooled to −78 C. Dimethylamine (17.1 g/379 mmol) was condensed via a CO₂/acetone bath and added to the reaction vessel. The mixture was allowed to warm to room temperature and was heated to 60 C. After 20 h, the reaction mixture was allowed to cool and was dissolved in ethyl ether. The ether solution was washed with H₂O, saturated aqueous NaCl, dried (MgSO₄), filtered, and concentrated in vacuo to give a white solid (28.5 g/96% yield). ¹H NMR confirmed the desired structure.

A 250-mL, 3-neck, round-bottom flask was equipped with N₂ gas adaptor and magnetic stirrer. The system was purged with N₂. The corresponding methoxy-compound (6.62 g/14.0 mmol) and CHCl₃ (150 mL) were added. The reaction mixture was cooled to −78 C., and boron tribromide (10.50 g/41.9 mmol) was added. The mixture was allowed to warm to room temperature After 4 h, the reaction mixture was cooled to 0 C. and was quenched with 10% K₂CO₃ (100 mL). After 10 min, the layers were separated, and the aqueous layer was extracted two times with ethyl ether. The CHCl₃ and ether extracts were combined, washed with saturated aqueous NaCl, dried (MgSO₄), filtered, and concentrated in vacuo to give the product (6.27 g/98% yield). ¹H NMR confirmed the desired structure.

In a 250 ml single neck round bottom Flask with stir bar place 2-diethylamineoethyl chloride hydochloride (fw 172.10 g/mole) Aldrich D8, 720-1 (2.4 mmol, 4.12 g), 34 ml dry ether and 34 ml of 1N KOH(aqueous). Stir 15 minutes and then separate by ether extraction and dry over anhydrous potassium carbonate.

In a separate 2-necked 250 ml round bottom flask with stir bar add sodium hydride (60% dispersion in mineral oil, 100 mg , 2.6 mmol) and 34 ml of DMF. Cool to ice temperature. Next add phenol product(previous step) 1.1 g (2.4 mmilomoles in 5 ml DMF and the ether solution prepared above. Heat to 40 C. for 3 days. The product which contained no starting material by TLC was diluted with ether and extracted with 1 portion of 5% NaOH, followed by water and then brine. The ether layer was dried over magnesium sulfate and isolated by removing ether by rotary evaporation (1.3 gms). The product may be further purified by chromatography (SiO2 99% ethyl acetate/1% NH4OH at 5 ml/min.). Isolated yield: 0.78 g (mass spec, and H1 NMR)

The product from step 10 (0.57 gms, 1.02 millimole fw 558.83 g/mole) and 1.6 gms iodoethane (10.02 mmol) was placed in 5 ml acetonitrile in a fischer-porter bottle and heated to 45 C. for 3 days. The solution was evaporated to dryness and redissolved in 5 mls of chloroform. Next ether was added to the chloroform solution and the resulting mixture was chilled. The desired product is isolated as a precipitate 0.7272 gms. Mass spec M−I=587.9, H NMR).

Example 1401

A 12-liter, 4-neck round-bottom flask was equipped with reflux condenser, N₂ gas adaptor, mechanical stirrer, and an addition funnel. The system was purged with N₂. A slurry of sodium hydride (126.0 g/4.988 mol) in toluene (2.5 L) was added, and the mixture was cooled to 6 C. A solution of 4-fluorophenol (560.5 g/5.000 mol) in toluene (2.5 L) was added via addition funnel over a period of 2.5 h. The reaction mixture was heated to reflux (100 C.) for 1h. A solution of 3-methoxybenzyl chloride (783.0 g/5.000 mol) in toluene (750 mL) was added via addition funnel while maintaining reflux. After 15 h. refluxing, the mixture was cooled to room temperature and poured into H₂O (2.5 L). After 20 min. stirring, the layers were separated, and the organic layer was extracted with a solution of potassium hydroxide (720 g) in MeOH (2.5 L). The MeOH layer was added to 20% aqueous potassium hydroxide, and the mixture was stirred for 30 min. The mixture was then washed 5 times with toluene. The toluene washes were extracted with 20% aq. KOH. All 20% aqueous KOH solutions were combined and acidified with concentrated HCl. The acidic solution was extracted three times with ethyl ether, dried over MgSO₄, filtered and concentrated in vacuo. The crude product was purified by Kugelrohr distillation to give a clear, colorless oil (449.0 g/39% yield). b.p.: 120-130 C./50 mtorrHg. ¹H NMR and MS [(M+H)⁺=233] confirmed desired 5 structure.

A 12-liter, 3-neck round-bottom flask was fitted with mechanical stirrer and N₂ gas adaptor. The system was purged with N₂. 4-Fluoro-2-(3-methoxybenzyl)-phenol (455.5 g/1.961 mol) and dimethylformamide were added. The solution was cooled to 6 C., and sodium hydride (55.5 g/2.197 mol) was added slowly. After warming to room temperature, dimethylthiocarbamoyl chloride (242.4 g/1.961 mol) was added. After 15 h, the reaction mixture was poured into H₂O (4.0 L), and extracted two times with ethyl ether. The combined organic layers were washed with H₂O and saturated aqueous NaCl, dried over MgSO₄, filtered, and concentrated in vacuo to give the product (605.3 g, 97% yield). ¹H NMR and MS [(M+H)⁺=320] confirm desired structure.

A 12-liter, round-bottom flask was equipped with N₂ gas adaptor, mechanical stirrer, and reflux condenser. The system was purged with N₂. 4-Fluoro-2-(3-methoxybenzyl)-phenyldimethylthiocarbamate (605.3 g/1.895 mol) and phenyl ether (2.0 kg) were added, and the solution was heated to reflux for 2 h. The mixture was stirred for 64 h. at room temperature and then heated to reflux for 2 h. After cooling to room temperature, MeOH (2.0 L) and THF (2.0 L) were added, and the solution was stirred for 15 h. Potassium hydroxide (425.9 g/7.590 mol) was added, and the mixture was heated to reflux for 4 h. After cooling to room temperature, the mixture was concentrated by rotavap, dissolved in ethyl ether (1.0 L), and extracted with H₂O. The aqueous extracts were combined, acidified with conc. HCl, and extracted with ethyl ether. The ether extracts were dried (MgSO₄), filtered, and concentrated in vacuo to give an amber oil (463.0 g, 98% yield). ¹H NMR confirmed desired structure.

A 5-liter, 3-neck, round-bottom flask was equipped with N₂ gas adaptor and mechanical stirrer. The system was purged with N₂. 4-Fluoro-2-(3-methoxybenzyl)-thiophenol (100.0 g/403.2 mmol) and 2-methoxyethyl ether (1.0 L) were added and the solution was cooled to 0C. Sodium hydride (9.68 g/383.2 mmol) was added slowly, and the mixture was allowed to warm to room temperature 2,2-Dibutylpropylene sulfate (110.89 g/443.6 mmol) was added, and the mixture was stirred for 64 h. The reaction mixture was concentrated by rotavap and dissolved in H₂O. The aqueous solution was washed with ethyl ether, and conc. H₂SO₄ was added. The aqueous solution was heated to reflux for 30 min, cooled to room temperature, and extracted with ethyl ether. The ether solution was dried (MgSO₄), filtered, and concentrated in vacuo to give an amber oil (143.94 g/85% yield). ¹H NMR and MS [(M+H)⁺=419] confirm the desired structure.

A 2-liter, 4-neck, round-bottom flask was equipped with N₂ gas adaptor, and mechanical stirrer. The system was purged with N₂. The corresponding alcohol (143.94 g/343.8 mmol) and CH₂Cl₂ (1.0 L) were added and cooled to 0 C. Pyridinium chlorochromate (140.53 g/651.6 mmol) was added. After 6 h., CH₂Cl₂ was added. After 20 min, the mixture was filtered through silica gel, washing with CH₂Cl₂. The filtrate was concentrated in vacuo to give a dark yellow-red oil (110.6 g, 77% yield). ¹H NMR and MS [(M+H)⁺=417] confirm the desired structure.

A 2-liter, 4-neck, round-bottom flask was equipped with N₂ gas adaptor and mechanical stirrer. The system was purged with N₂. The corresponding sulfide (110.6 g/265.5 mmol) and CH₂Cl₂ (1.0 L) were added. The solution was cooled to 0 C., and 3-chloroperbenzoic acid (158.21 g/531.7 mmol) was added portionwise. After 30 min, the reaction mixture was allowed to warm to room temperature After 3.5 h, the reaction mixture was cooled to 0 C. and filtered through a fine fritted funnel. The filtrate was washed with 10% aqueous K₂CO₃. An emulsion formed which was extracted with ethyl ether. The organic layers were combined, dried (MgSO₄), filtered, and concentrated in vacuo to give the product (93.2 g, 78% yield). ¹H NMR confirmed the desired structure.

A 2-liter, 4-neck, round-bottom flask was equipped with N₂ gas adaptor, mechanical stirrer, and a powder addition funnel. The system was purged with N₂. The corresponding aldehyde (93.2 g/208 mmol) and THF (1.0 L) were added, and the mixture was cooled to 0 C.

Potassium tert-butoxide (23.35 g/208.1 mmol) was added via addition funnel. After 1 h, 10% aq/HCl (1.0 L) was added. After 1 h, the mixture was extracted three times with ethyl ether, dried (MgSO₄), filtered, and concentrated in vacuo. The crude product was purified by recrystallized from 80/20 hexane/ethyl acetate to give a white solid (32.18 g). The mother liquor was concentrated in vacuo and recrystallized from 95/5 toluene/ethyl acetate to give a white solid (33.60 g, combined yield: 71%). ¹H NMR confirmed the desired product.

A Fisher porter bottle was fitted with N₂ line and magnetic stirrer. The system was purged with N₂. The corresponding fluoro-compound (28.1 g/62.6 mmol) was added, and the vessel was sealed and cooled to −78 C. Dimethylamine (17.1 g/379 mmol) was condensed via a CO₂/acetone bath and added to the reaction vessel. The mixture was allowed to warm to room temperature and was heated to 60C. After 20 h, the reaction mixture was allowed to cool and was dissolved in ethyl ether. The ether solution was washed with H₂O, saturated aqueous NaCl, dried over MgSO₄, filtered, and concentrated in vacuo to give a white solid (28.5 g/96% yield). ¹H NMR confirmed the desired structure.

A 250-mL, 3-neck, round-bottom flask was equipped with N₂ gas adaptor and magnetic stirrer. The system was purged with N₂. The corresponding methoxy-compound (6.62 g/14.0 mmol) and CHCl₃ (150 mL) were added. The reaction mixture was cooled to −78 C., and boron tribromide (10.50 g/41.9 mmol) was added. The mixture was allowed to warm to room temperature After 4 h, the reaction mixture was cooled to 0 C. and was quenched with 10% K₂CO₃ (100 mL). After 10 min, the layers were separated, and the aqueous layer was extracted two times with ethyl ether. The CHCl₃ and ether extracts were combined, washed with saturated aqueous NaCl, dried over MgSO₄, filtered, and concentrated in vacuo to give the product (6.27 g/98% yield). ¹H NMR confirmed the desired structure.

In a 250 ml single neck round bottom flask with stir bar place 2-diethylamineoethyl chloride hydochloride (fw 172.10 g/mole) Aldrich D8, 720-1 (2.4 millimoles, 4.12 g), 34 ml dry ether and 34 ml of 1N KOH (aqueous). Stir 15 minutes and then separate by ether extraction and dry over anhydrous potassium carbonate.

In a separate 2-necked 250 ml round bottom flask with stir bar add sodium hydride (60% dispersion in mineral oil, 100 mg, (2.6 mmol) and 34 ml of DMF. Cool to ice temperature. Next add phenol product (previous step) 1.1 g (2.4 mmol in 5 ml DMF and the ether solution prepared above. Heat to 40 C. for 3 days. The product which contained no starting material by TLC was diluted with ether and extracted with 1 portion of 5% NaOH, followed by water and then brine. The ether layer was dried over Magnesium sulfate and isolated by removing ether by rotary evaporation (1.3 gms). The product may be further purified by chromatography (silica 99% ethyl acetate/1% NH4OH at 5 ml/min.). Isolated yield: 0.78 g (mass spec , and H1 NMR)

The product from step 10 (0.57 gms, 1.02 millimole fw 558.83 g/mole) and iodoethane (1.6 gms (10.02 mmilimoles)was place in 5 ml acetonitrile in a Fischer-Porter bottle and heated to 45 C. for 3 days. The solution was evaporated to dryness and redissolved in 5 mls of chloroform. Next ether was added to the chloroform solution and the resulting mixture was chilled. The desired product is isolated as a precipitate 0.7272 gms. Mass spec M−I=587.9, ¹H NMR).

Example 1402

(4R-cis)-5-[[5-[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]pentyl]thio]-1H-tetrazole-1-acetic acid

Step 1. Preparation of 4-fluoro-2-((4-methoxyphenyl)methyl)-phenol

To a stirred solution of 23.66 g of 95% sodium hydride (0.94 mol) in 600 mL of dry toluene was added 100.0 g of 4-fluorophenol (0.89 mol) at 0° C. The mixture was stirred at 90° C. for 1 hour until gas evolution stopped. The mixture was cooled down to room temperature and a solution of 139.71 g of 3-methoxybenzyl chloride (0.89 mol) in 400 mL of dry toluene was added. After refluxing for 24 hours, the mixture was cooled to room temperature and quenched with 500 mL of water. The organic layer was separated, dried over MgSO₄, and concentrated under high vacuum. The remaining starting materials were removed by distillation. The crude dark red oil was filtered through a layer of 1 L of silica gel with neat hexane to yield 53.00 g (25.6%) of the product as a pink solid: ¹H NMR (CDCl₃) δ6 3.79 (s, 3H), 3.90 (s, 2H), 4.58 (s, 1H), 6.70-6.74 (m, 1H), 6.79-6.88 (m, 4H), 7.11-7.16 (m, 2H).

Step 2. Preparation of 4-fluoro-2-((4-methoxyphenyl)methyl)-thiophenol

Step 2a. Preparation of Thiocarbamate

To a stirred solution of 50.00 g (215.30 mmol) of 4-fluoro-2-((4-methoxyphenyl)methyl)-phenol in 500 mL of dry DMF was added 11.20 g of 60% sodium hydride dispersion in mineral oil (279.90 mmol) at 2° C. The mixture was allowed to warm to room temperature and 26.61 g of dimethylthiocarbamoyl chloride (215.30 mmol) was added. The reaction mixture was stirred at room temperature overnight. The mixture was quenched with 100 mL of water in an ice bath. The solution was extracted with 500 mL of diethyl ether. The ether solution was washed with 500 mL of water and 500 mL of brine. The ether solution was dried over MgSO₄ and stripped to dryness. The crude product was filtered through a plug of 500 mL silica gel using 5% ethyl acetate/hexane to yield 48.00 g (69.8%) of the product as a pale white solid: ¹H NMR (CDCl₃) δ3.21 (s, 3H), 3.46 (s, 3H), 3.80 (s, 3H), 3.82 (s, 2H), 6.78-6.86 (m, 3H), 6.90-7.00 (m, 2H), 7.09 (d, J=8.7 Hz, 2H).

Step 2b. Rearrangement and Hydrolysis of Thiocarbamate to 4-fluoro-2-((4-methoxyphenyl)methyl)-thiophenol

A stirred solution of 48.00 g (150.29 mmol) of thiocarbamate (obtained from Step 2a) in 200 mL of diphenyl ether was refluxed at 270° C. overnight. The solution was cooled down to room temperature and filtered through 1 L of silica gel with 2 L of hexane to remove phenyl ether. The rearrangement product was washed with 5% ethyl acetate/hexane to give 46.00 g (95.8%) of the product as a pale yellow solid: ¹H NMR (CDCl₃) δ3.02 (s, 3H), 3.10 (s, 3H), 3.80 (s, 3H), 4.07 (s, 2H), 6.82-6.86 (m, 3H), 6.93 (dt, J=8.4 Hz, 2.7 Hz, 1H), 7.08 (d, J=8.7 Hz, 2H), 7.49 (dd, J=6.0 Hz, 8.7 Hz, 1H)

To a solution of 46.00 g (144.02 mmol) of the rearrangement product (above) in 200 mL of methanol and 200 mL of THF was added 17.28 g of NaOH (432.06 mmol). The mixture was refluxed under nitrogen overnight. The solvents were evaporated off and 200 mL of water was added. The aqueous solution was washed with 200 mL of diethyl ether twice and placed in an ice bath. The aqueous mixture was acidified to pH 6 with concentrated HCl solution. The solution was extracted with 300 mL of diethyl ether twice. The ether layers were combined, dried over MgSO₄ and stripped to dryness to afford 27.00 g (75.5%) of the product as a brown oil: ¹H NMR (CDCl₃) δ3.24 (s, 1H), 3.80 (s, 3H), 3.99 (s, 2H), 6.81-6.87 (m, 4H), 7.09 (d, J=8.7 Hz, 2H), 7.27-7.33 (m, 1H).

Step 3. Preparation of Dibutyl Cyclic Sulfate

Step 3a. Preparation of 2,2-dibutyl-1,3-propanediol

To a stirred solution of di-butyl-diethylmalonate (Aldrich) (150 g, 0.55 mol in dry THF (700 ml) in an acetone/dry ice bath was added LAH (1 M THF) 662 ml (1.2 eq., 0.66 mol) dropwise maintaining the temperature between −20 to 0° C. The reaction was stirred at RT overnight. The reaction was cooled to −20° C. and 40 ml of water, and 80 mL of 10% NaOH and 80 ml of water were added dropwise. The resulting suspension was filtered. The filtrate was dried over sodium sulphate and concentrated in vacuo to give diol 98.4 g (yield 95%) as an oil. MS spectra and proton and carbon NMR spectra were consistent with the product.

Step 3b. Preparation of Dibutyl Cyclic Sulfite

A solution of 2,2-dibutyl-1,3-propanediol (103 g, 0.548 mol, obtained from Step 3a) and triethylamine (221 g, 2.19 mol) in anhydrous methylene chloride (500 ml) was stirred at 0° C. under nitrogen. To the mixture, thionyl chloride (97.8 g, 0.82 mol) was added dropwise and within 5 min the solution turned yellow and then black when the addition was completed within half an hour. The reaction mixture was stirred for 3 hrs. at 0° C. GC showed that there was no starting material left. The mixture was washed with ice water twice then with brine twice. The organic phase was dried over magnesium sulfate and concentrated under vacuum to give 128 g (100%) of the dibutyl cyclic sulfite as a black oil. Mass spectrum (MS) was consistent with the product.

Step 3c. Oxidation of Dibutyl Cyclic Sulfite to Dibutyl Cyclic Sulfate

To a solution of the dibutyl cyclic sulfite (127.5 g, 0.54 mol, obtained from Step 3b) in 600 ml acetonitrile and 500 ml of water cooled in an ice bath under nitrogen was added ruthenium (III) chloride (1 g) and sodium periodate (233 g, 1.08 mol). The reaction was stirred overnight and the color of the solution turned black. GC showed that there was no starting material left. The mixture was extracted with 300 ml of ether and the ether extract was washed three times with brine. The organic phase was dried over magnesium sulfate and passed through celite. The filtrate was concentrated under vacuum and to give 133 g (97.8%) of the dibutyl cyclic sulfate as an oil. Proton and carbon NMR and MS were consistent with the product.

Step 4. Preparation of aryl-3-hydroxypropylsulfide

To a stirred solution of 27.00 g (108.73 mmol) of 4-fluoro-2-((4-methoxyphenyl)methyl)thiophenol (obtained from Step 2) in 270 mL of diglyme was added 4.35 g of 60% sodium hydride dispersion in mineral oil (108.73 mmol) at 0° C. After gas evolution ceased, 29.94 g (119.60 mmol) of the dibutyl cyclic sulfate (obtained from Step 3c) was added at 0° C. and stirred for 10 minutes. The mixture was allowed to warm up to room temperature and stirred overnight. The solvent was evaporated and 200 mL of water was added. The solution was washed with 200 mL of diethyl ether and added 25 mL of concentrated sulfuric acid to make a 2.0 M solution that was refluxed overnight. The solution was extracted with ethyl acetate and the organic solution was dried over MgSO₄ and concentrated in vacuo. The crude aryl-3-hydroxypropylsulfide was purified by silica gel chromatography (Waters Prep 500) using 8% ethyl acetate/hexane to yield 33.00 g (72.5%) of the product as a light brown oil: ¹H NMR (CDCl₃) δ0.90 (t, J=7.1 Hz, 6H), 1.14-1.34 (m, 12H), 2.82 (s, 2H), 3.48 (s, 2H), 3.79 (s, 3H), 4.10 (S, 2H), 6.77-6.92 (m, 4H), 7.09 (d, J=8.7 Hz, 2H), 7.41 (dd, J=8.7 Hz, 5.7 Hz, 1H).

Step 5. Preparation of Enantiomerically-enriched Aryl-3-hydroxypropylsulfoxide

To a stirred solution of 20.00 g (47.78 mmol) of aryl-3-hydroxypropylsulfide (obtained from Step 4) in 1 L of methylene chloride was added 31.50 g of 96% (1R)-(−)-(8,8-dichloro-10-camphor-sulfonyl)oxaziridine (100.34 mmol, Aldrich) at 2° C. After all the oxaziridine dissolved the mixture was placed into a −30° C. freezer for 72 hours. The solvent was evaporated and the crude solid was washed with 1 L of hexane. The white solid was filtered off and the hexane solution was concentrated in vacuo. The crude oil was purified on a silica gel column (Waters Prep 500) using 15% ethyl acetate/hexane to afford 19.00 g (95%) of the enantiomerically-enriched aryl-3-hydroxypropylsulfoxide as a colorless oil: ¹H NMR (CDCl₃) δ0.82-0.98 (m, 6H), 1.16-1.32 (m, 12H), 2.29 (d, J=13.8 Hz, 1H), 2.77 (d, J=13.5 Hz, 1H), 3.45 (d, J=12.3 Hz, 1H), 3.69 (d, J=12.3 Hz, 1H), 3.79 (s, 3H), 4.02 (q, J=15.6 Hz, 1H), 6.83-6.93 (m, 3H), 7.00 (d, J=8.1 Hz, 2H), 7.18-7.23 (m, 1H), 7.99-8.04 (m, 1H). Enantiomeric excess was determined by chiral HPLC on a (R,R)-Whelk-O column using 5% ethanol/hexane as the eluent. It showed to be 78% e.e. with the first eluting peak as the major product.

Step 6. Preparation of Enantiomerically-enriched Aryl-3-propanalsulfoxide

To a stirred solution of 13.27 g of triethylamine (131.16 mmol, Aldrich) in 200 mL dimethyl sulfoxide were added 19.00 g (43.72 mmol) of enantiomerically-enriched aryl-3-hydroxypropylsulfoxide (obtained from Step 5) and 20.96 g of sulfur trioxide-pyridine (131.16 mmol, Aldrich) at room temperature. After the mixture was stirred at room temperature for 48 hours, 500 mL of water was added to the mixture and stirred vigorously. The mixture was then extracted with 500 mL of ethyl acetate twice. The ethyl acetate layer was separated, dried over MgSO₄, and concentrated in vacuo. The crude oil was filtered through 500 mL of silica gel using 15% ethyl acetate/hexane to give 17.30 g (91%) of the enantiomerically-enriched aryl-3-propanalsulfoxide as a light orange oil: ¹H NMR (CDCl₃) δ0.85-0.95 (m, 6H), 1.11-1.17 (m, 4H), 1.21-1.39 (m, 4H), 1.59-1.76 (m, 4H), 1.89-1.99 (m, 1H), 2.57 (d, J=14.1 Hz, 1H), 2.91 (d, J=13.8 Hz, 1H), 3.79 (s, 3H), 3.97 (d, J=15.9 Hz, 1H), 4,12 (d, J=15.9 Hz, 1H), 6.84-6.89 (m, 3H), 7.03 (d, J=8.4 Hz, 2H), 7.19 (dt, J=8.4 Hz, 2.4 Hz, 1H), 8.02 (dd, J=8.7 Hz, 5.7 Hz, 1H), 9.49 (s, 1H).

Step 7. Preparation of the Enantiomerically-enriched Tetrahydrobenzothiepine-1-oxide (4R,5R)

To a stirred solution of 17.30 g (39.99 mmol) of enantiomerically-enriched aryl-3-propanalsulfoxide (obtained from Step 6) in 300 mL of dry THF at −15° C. was added 48 mL of 1.0 M potassium t-butoxide in THF (1.2 equivalents) under nitrogen. The solution was stirred at −15° C. for 4 hours. The solution was then quenched with 100 mL of water and neutralized with 4 mL of concentrated HCl solution at 0 C. The THF layer was separated, dried over MgSO₄, and concentrated in vacuo. The enantiomerically-enriched tetrahydrobenzothiepine-1-oxide (4R,5R) was purified by silica gel chromatography (Waters Prep 500) using 15% ethyl acetate/hexane to give 13.44 g (77.7%) of the product as a white solid: ¹H NMR (CDCl₃) δ0.87-0.97 (m, 6H), 1.16-1.32 (m, 4H), 1.34-1.48 (m, 4H), 1.50-1.69 (m, 4H), 1.86-1.96 (m, 1H), 2.88 (d, J=13.0 Hz, 1H), 3.00 (d, J=13.0 Hz, 1H), 3.85 (s, 3H), 4.00 (s, 1H), 4.48 (s, 1H), 6.52 (dd, J=9.9 Hz, 2.4 Hz, 1H), 6.94 (d, J=9 Hz, 2H), 7.13 (dt, J=8.4 Hz, 2.4 Hz, 1H), 7.38 (d, J=8.7 Hz, 2H), 7.82 (dd, J=8.7 Hz, 5.7 Hz, 1H).

Step 8. Preparation of Enantiomerically-enriched Tetrahydrobenzothiepine-1,1-dioxide (4R,5R)

To a stirred solution of 13.44 g (31.07 mmol) of enantiomerically-enriched tetrahydrobenzothiepine-1-oxide (obtained from Step 7) in 150 mL of methylene chloride was added 9.46 g of 68% m-chloroperoxybenzoic acid (37.28 mmol, Sigma) at 0° C. After stirring at 0° C. for 2 hours, the mixture was allowed to warm up to room temperature and stirred for 4 hours. 50 mL of saturated Na₂SO₃ was added into the mixture and stirred for 30 minutes. The solution was then neutralized with 50 mL of saturated NaHCO₃ solution. The methylene chloride layer was separated, dried over MgSO₄, and concentrated in vacuo to give 13.00 g (97.5%) of the enantiomerically-enriched tetrahydrobenzothiepine-1,1-dioxide (4R,5R) as a light yellow solid: ¹H NMR (CDCl₃) δ0.89-0.95 (m, 6H), 1.09-1.42 (m, 12H), 2.16-2.26 (m, 1H), 3.14 (q, J=15.6 Hz, 1H), 3.87 (s, 3H), 4.18 (s, 1H), 5.48 (s, 1H), 6.54 (dd, J=10.2 Hz, 2.4 Hz, 1H), 6.96-7.07 (m, 3H), 7.40 (d, J=8.1 Hz, 2H), 8.11 (dd, J=8.6 Hz, 5.9 Hz, 1H).

Step 9. Preparation of Enantiomerically-enriched 7-(dimethylamino)tetrahydrobenzothiepine-1,1-dioxide (4R,5R)

To a solution of 13.00 g (28.98 mmol) of enantiomerically-enriched tetrahydrobenzothiepine-1,1-dioxide (obtained from Step 8) in 73 mL of dimethylamine (2.0 M in THF, 146 mmol) in a Parr Reactor was added about 20 mL of neat dimethylamine. The mixture was sealed and stirred at 110° C. overnight, and cooled to ambient temperature. The excess dimethylamine was evaporated. The crude oil was dissolved in 200 mL of ethyl acetate and washed with 100 mL of water, dried over MgSO₄ and concentrated in vacuo. Purification on a silica gel column (Waters Prep 500) using 20% ethyl acetate/hexane gave 12.43 g (90.5%) of the enantiomerically-enriched 7-(dimethylamino)tetrahydrobenzothiepine-1,1-dioxide (4R,5R) as a colorless solid: ¹H NMR (CDCl₃) δ0.87-0.93 (m, 6H), 1.10-1.68 (m, 12H), 2.17-2.25 (m, 1H), 2.81 (s, 6H), 2.99 (d, J=15.3 Hz, 1H), 3.15 (d, J=15.3 Hz, 1H), 3.84 (s, 3H), 4.11 (d, J=7.5 Hz, 1H), 5.49 (s, 1H), 5.99 (d, J=2.4 Hz, 1H), 6.51 (dd, J=8.7 Hz, 2.4 Hz, 1H), 6.94 (d, J=8.7 Hz, 2H), 7.42 (d, J=8.4 Hz, 2H), 7.90 (d, J=8.7 Hz, 1H). The product was determined to have 78% e.e. by chiral HPLC on a Chiralpak AD column using 5% ethanol/hexane as the eluent. Recrystallization of this solid from ethyl acetate/hexane gave 1.70 g of the racemic product. The remaining solution was concentrated and recrystallized to give 9.8 g of colorless solid. Enantiomeric excess of this solid was determined by chiral HPLC on a Chiralpak AD column using 5% ethanol/hexane as the eluent. It showed to have 96% e.e with the first eluting peak as the major product.

Step 10: Demethylation of 5-(4′-methoxyphenyl)-7-(dimethylamino)tetrahydrobenzothiepine-1,1-dioxide (4R,5R)

To a solution of 47 g (99 mmol) of enantiomeric-enriched (dimethylamino)tetrahydrobenzothiepine-1,1-dioxide (obtained from Step 9) in 500 mL of methylene chloride at −10° C. was added dropwise a solution of boron tribromide (297 mL, 1M in methylene chloride, 297 mmol), and the resulting solution was stirred cold (−5° C. to 0° C.) for 1 hour or until the reaction was complete. The reaction was cooled in an acetone-dry ice bath at −10° C., and slowly quenched with 300 mL of water. The mixture was warmed to 10° C., and further diluted with 300 mL of saturated sodium bicarbonate solution to neutralize the mixture. The aqueous layer was separated and extracted with 300 mL of methylene chloride, and the combined extracts were washed with 200 mL of water, brine, dried over MgSO₄ and concentrated in vacuo. The residue was dissolved in 500 mL of ethyl acetate and stirred with 50 mL of glacial acetic acid for 30 minutes at ambient temperature. The mixture was washed twice with 200 mL of water, 200 mL of brine, dried over MgSO₄ and concentrated in vacuo to give the crude 4-hydroxyphenyl intermediate. The solid residue was recrystallized from methylene chloride to give 37.5 g (82%) of the desired 5-(4′-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzothiepine-1,1-dioxide as a white solid: ¹H NMR (CDCl₃) δ0.84-0.97 (m, 6H), 1.1-1.5 (m, 10H), 1.57-1.72 (m, 1H), 2.14-2.28 (m, 1H), 2.83 (s, 6H), 3.00 (d, J=15.3 Hz, 1H), 3.16 (d, J=15.3 Hz, 1H), 4.11 (s, 2H), 5.48 (s, 1H), 6.02 (d, J=2.4 Hz, 1H), 6.55 (dd, J=9, 2.4 Hz, 1H), 6.88 (d, 8,7 Hz, 2H), 7.38 (d, J=8.7 Hz, 2H), 7.91 (d, J=9 Hz, 2H).

Alternatively, enantiomeric-enriched 5-(4′-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzothiepine-1,1-dioxide, the intermediate just described, can be prepared via non-enantioselective synthesis followed by chiral chromatography separation. Oxidation of aryl-3-hydroxypropylsulfide (obtained from Step 4) with m-chloroperbenzoic acid (under the similar conditions as in Step 8, but with 2.2 equivalent of m-CPBA) gave the racemic sulfone intermediate. The sulfone was carried through the synthetic sequences (under the same conditions as in Step 7 and Step 9) to give the racemic 5-(4′-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzothiepine-1,1-dioxide. The two enantiomers were further separated into the desired enantiomeric-enriched 5-(4′-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzothiepine-1,1-dioxide by appropriate chiral chromatographic purification.

Step 11: Preparation of Ester Intermediate

To a solution of 1.0 g (2.18 mmol) of 5-(4′-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzothiepine-1,1-dioxide (obtained from Step 10) in 10 mL dimethylformamide was added 60 mg (2.38 mmol) of 95% sodium hydride and stirred for 15 minutes. To the reaction mixture was added 400 μL (2.52 mmol) of benzyl 2-bromoacetate and stirred for two hours. Water was added to the reaction mixture, extracted with ethyl acetate, washed with brine, dried over magnesium sulfate, filtered and the solvent evaporated to afford 1.30 g (98%) of the ester intermediate: ¹H NMR (CDCl₃) δ0.88-0.94 (m, 6H), 1.13-1.46 (m, 10H), 1.60-1.64 (m, 1H), 2.20-2.24 (m, 1H), 2.81 (s, 6H), 3.00 (d, J=15.1 Hz, 1H), 3.16 (t, J=15.1 Hz, 1H), 4.11 (s, 1H), 5.26 (s, 2H), 5.49 (s, 1H), 6.04 (d, J=2.4 Hz, 1H), 6.63 (dd, J=8.9, 2.4 Hz, 1H), 6.95 (d, J=8.7 Hz, 2H), 7.37 (s, 5H), 7.42 (d, J=8.5 Hz, 2H), 7.93 (d, J=8.9 Hz, 1H).

Step 12: Preparation of Acid

A solution of 1.30 g (2.14 mmol) of ester intermediate (obtained from Step 1) in 40 mL ethanol with 10% palladium on carbon was placed under an atmosphere of hydrogen gas (40 psi) for three hours. The reaction mixture was filtered through celite and the solvent was evaporated to afford the desired title compound as a white solid: mp 119-123° C.; ¹H NMR (CDCl₃) δ0.89-0.94 (m, 6H), 1.19-1.43 (m, 10H), 1.61-1.65 (m, 1H), 2.17-2.21 (m, 1H), 2.85 (s, 6H), 3.02 (d, J=15.1 Hz, 1H), 3.17 (t, J=14.9 Hz, 1H), 4.12 (s, 1H), 4.72 (s, 2H), 5.51 (s, 1H), 6.17 (s, 1H), 6.74 (d, J=9.1 Hz, 1H), 6.99 (d, J=8.3 Hz, 2H), 7.46 (d, J=8.5 Hz, 2H), 7.97 (d, J=8.7 Hz, 1H). HRMS. Calc'd for C₂₈H₄₀NO₆S: 518.2576. Found: 518.2599.

Example 1403

(4R-cis)-N-[[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxyacetyl]glycine

Step 1: Preparation of Glycine Ester Intermediate

To a solution of 6.4 g (13.9 mmol) of 5-(4′-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzothiepine-1,1-dioxide (obtained from Example 1402, Step 10) and 2.9 g (21.0 mmol) of potassium carbonate in 100 ml of acetone was added 3.8 g (21.0 mmol) of N-(chloroacetyl)glycine ethyl ester and 50 mg (0.14 mmol) of tetrabutylammonium iodide. The reaction was heated to reflux for 2 days, cooled to ambient temperature and stirred for 20 hours, then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over MgSO₄, and concentrated in vacuo. Purification by silica gel chromatography (Waters Prep-500) using 50% ethyl acetate/hexanes afforded 7.5 g (90%) of glycine ester intermediate as a white foam: ¹H NMR (CDCl₃) δ0.86-0.98 (m, 6H), 1.04-1.56 (m, 13H), 1.58-1.71 (m, 1H), 2.14-2.29 (m, 1H), 2.73 (s, 6H), 3.08 (AB_(q), J_(AB)=15.3 Hz, J=48.9 Hz, 2H), 4.06-4.19 (m, 6H), 4.25 (q, J=7.0 Hz, 2H), 4.57 (s, 2H), 5.50 (s, 1H), 5.98 (s, 1H), 6.56 (d, J=8.6 Hz, 1H), 6.98 (d, J=8.5 Hz, 2H), 7.17 (s, 1H), 7.47 (d, J=8.3 Hz, 2H), 7.91 (d, J=8.7 Hz, 1H).

Step 2: Preparation of Acid

A solution of 7.3 g (12.1 mmol) of glycine ester intermediate (obtained from Step 1) and 1.5 g LiOH.H₂O (36.3 mmol) in 60 mL of THF and 60 mL of water was heated to 45° C. for 2 hours. This was then cooled to ambient temperature, acidified with 1 N HCl and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over MgSO₄, and concentrated in vacuo. Purification by recrystallization from ethyl acetate gave 5.45 g (78%) of the desired title compound as a white crystalline solid: mp 149-150° C.; ¹H NMR (CD₃OD) δ0.88-0.98 (m, 6H), 1.06-1.56 (m, 10H), 1.70-1.84 (m, 1H), 2.06-2.20 (m, 1H), 2.79 (s, 6H), 3.11 (AB_(q), J_(AB)=15.3 Hz, J=21.6 Hz, 2H), 4.01 (s, 2H), 4.07 (s, 1H), 4.61 (s, 2H), 5.31 (s, 1H), 6.04 (s, 1H), 6.57 (d, J=9.0 Hz, 1H), 7.08 (d, J=7.8 Hz, 2H), 7.44 (d, J=8.1 Hz, 2H), 7.76 (d, J=9.0 Hz, 1H), 8.42 (m, 1H). HRMS (ES+) Calc'd for C₃₀H₄₂N₂O₇S: 575.2712. Found: 575.2790. Anal. Calc'd for: C₃₀H₄₂N₂O₇S C, 62.69; H, 7.37; N, 4.87. Found: C, 62.87; H, 7.56; N, 4.87.

Example 1403

(4R-cis)-N-[[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxyacetyl]glycine

Step 1: Preparation of Glycine Ester Intermediate

To a solution of 6.4 g (13.9 mmol) of 5-(4′-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzothiepine-1,1-dioxide (obtained from Example 1402, Step 10) and 2.9 g (21.0 mmol) of potassium carbonate in 100 ml of acetone was added 3.8 g (21.0 mmol) of N-(chloroacetyl)glycine ethyl ester and 50 mg (0.14 mmol) of tetrabutylammonium iodide. The reaction was heated to reflux for 2 days, cooled to ambient temperature and stirred for 20 hours, then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over MgSO₄, and concentrated in vacuo. Purification by silica gel chromatography (Waters Prep-500) using 50% ethyl acetate/hexanes afforded 7.5 g (90%) of glycine ester intermediate as a white foam: ¹H NMR (CDCl₃) δ0.86-0.98 (m, 6H), 1.04-1.56 (m, 13H), 1.58-1.71 (m, 1H), 2.14-2.29 (m, 1H), 2.73 (s, 6H), 3.08 (AB_(q), J_(AB)=15.3 Hz, J=48.9 Hz, 2H), 4.06-4.19 (m, 6H), 4.25 (q, J=7.0 Hz, 2H), 4.57 (s, 2H), 5.50 (s, 1H), 5.98 (s, 1H), 6.56 (d, J=8.6 Hz, 1H), 6.98 (d, J=8.5 Hz, 2H), 7.17 (s, 1H), 7.47 (d, J=8.3 Hz, 2H), 7.91 (d, J=8.7 Hz, 1H).

Step 2: Preparation of Acid

A solution of 7.3 g (12.1 mmol) of glycine ester intermediate (obtained from Step 1) and 1.5 g LiOH.H₂O (36.3 mmol) in 60 mL of THF and 60 mL of water was heated to 45° C. for 2 hours. This was then cooled to ambient temperature, acidified with 1 N HCl and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over MgSO₄, and concentrated in vacuo. Purification by recrystallization from ethyl acetate gave 5.45 g (78%) of the desired title compound as a white crystalline solid: mp 149-150° C.; ¹H NMR (CD₃OD) δ0.88-0.98 (m, 6H), 1.06-1.56 (m, 10H), 1.70-1.84 (m, 1H), 2.06-2.20 (m, 1H), 2.79 (s, 6H), 3.11 (AB_(q), J_(AB)=15.3 Hz, J=21.6 Hz, 2H), 4.01 (s, 2H), 4.07 (s, 1H), 4.61 (s, 2H), 5.31 (s, 1H), 6.04 (s, 1H), 6.57 (d, J=9.0 Hz, 1H), 7.08 (d, J=7.8 Hz, 2H), 7.44 (d, J=8.1 Hz, 2H), 7.76 (d, J=9.0 Hz, 1H), 8.42 (m, 1H). HRMS(ES+) Calc'd for C₃₀H₄₂N₂O₇S: 575.2712. Found: 575.2790. Anal. Calc'd for: C₃₀H₄₂N₂O₇S C, 62.69; H, 7.37; N, 4.87. Found: C, 62.87; H, 7.56; N, 4.87.

Example 1404

(4R-cis)-5-[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]pentanoic acid

Step 1: Preparation of Ester Intermediate

A solution of 5-(4′-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzothiepine-1,1-dioxide (1.0 g, 2.2 mmol, obtained from Example 1402, Step 10) in acetone (10 mL) at 25° C. under N₂ was treated with powdered K₂CO₃ (0.45 g, 3.3 mmol, 1.5 eq.), benzyl 5-bromovalerate (0.88 g, 3.3 mmol, 1.5 eq.) and a catalytic amount of tetra-n-butylammonium iodide (2 mg), and the resulting solution was stirred at 65° C. for 24 hours. The pale amber slurry was cooled to 25° C. and was concentrated in vacuo to provide a yellow residue. Purification by flash chromatography (2.4×30 cm silica, 20-40% EtOAc/hexane) afforded the ester intermediate (1.2 g, 86%) as a colorless oil: ¹H NMR (CDCl₃) δ0.91 (m, 6H), 1.11-1.47 (br m, 10H), 1.64 (m, 1H), 1.86 (m, 2H), 2.21 (m, 1H), 2.47 (m, 2H), 2.81 (s, 6H), 3.05 (ABq, J=15.1 Hz, J=47.7 Hz, 2H), 4.10 (d, J=7.9 Hz, 1H), 5.13 (s, 2H), 5.47 (s, 1H), 6.00 (d, J=2.5 Hz, 1H), 6.50 (dd, J=8.9, 2.5 Hz, 1H), 6.91 (d, J=8.7 Hz, 2H), 7.36 (m, 5H), 7.40 (d, J=8.5 Hz, 2H), 7.86 (d, J=8.9 Hz, 1H); HRMS. Calc'd for C₃₈H₅₁NO₆S: 650.3515. Found: 650.3473.

Step 2: Preparation of Acid

A solution of the ester intermediate (0.99 g, 1.5 mmol, obtained from Step 1) in ethanol (7.5 mL) at 25° C. was treated with 5% palladium on carbon (0.15 g, 10 wt %) then stirred under an atmosphere (1 atm) of H₂ via hydrogen balloon. Every 10 min, hydrogen gas was bubbled through the slurry for 1 min, for a total reaction time of 4 hours. The slurry was placed under an atmosphere of N₂ and nitrogen was bubbled through the reaction mixture for 10 min. The mixture was filtered through a plug of Celite® (10 g) and concentrated in vacuo to give a white foam. Purification by flash chromatography (2.6×25 cm silica, 1.5% EtOH/CH₂Cl₂) afforded the desired title compound (0.54 g, 63%) as a white foam: mp: 76-79° C.; ¹H NMR (CDCl₃) δ0.90 (m, 6H), 1.10-1.46 (br m, 10H), 1.62 (m, 1H), 1.87 (m, 4H), 2.20 (m, 1H), 2.45 (m, 2H), 2.81 (s, 6H), 3.05 (ABq, J=15.1 Hz, J=49.7 Hz, 2H), 4.00 (s, 2H), 4.09 (s, 1H), 5.45 (s, 1H), 5.99 (d, J=2.4 Hz, 1H), 6.48 (dd, J=8.9, 2.4 Hz, 1H), 6.91 (d, J=8.7 Hz, 2H), 7.39 (m, 5H), 7.39 (d, J=8.3 Hz, 2H), 7.84 (d, J=8.9 Hz, 1H); HRMS. Calc'd for C₃₁H₄₅NO₆S: 560.3046. Found: 560.3043.

Example 1405

(4R-cis)-4-[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy-1-butanesulfonamide

Step 1: Preparation of Sulfonic Acid Intermediate

A solution of 7.4 g (16.1 mmol) of 5-(4′-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzothiepine-1,1-dioxide (obtained from Example 1402, Step 10) in acetone (35 mL) at 25° C. under N₂ was treated with powdered potassium carbonate (3.3 g, 24.1 mmol, 1.5 equiv.) and 1,4-butane sultone (2.5 mL, 24.1 mmol, 1.5 equiv.) and stirred and heated at 65° C. for 64 h. The solution was allowed to cool to 25° C. and quenched by the addition of water (50 mL), until a homogeneous mixture was obtained. The clear and colorless solution was added dropwise to a 4 N HCl solution cooled to 0° C. over a 30 min period. The mixture was vigorously stirred for 4 h then allowed to warm to ambient temperature and stirred for an additional 16 h. The resultant white precipitate was filtered and washed with water and dried in vacuo to provide 8.8 g (92%) of the desired sulfonic acid as a white solid. A portion of the white solid was recrystallized from CH₃CN/hexane to give the desired sulfonic acid as colorless needles: mp 229-236° C. (decomposed); ¹H NMR (DMSO-d₆) δ0.82 (m, 6H), 1.02-1.33 (br m, 10H), 1.59 (m, 1H), 1.73 (m, 4H), 2.00 (s, 1H), 2.48 (m, 2H), 2.71 (s, 6H), 2.98 (s, 1H), 3.86 (s, 1H), 3.93 (m, 2H), 5.08 (s, 1H), 5.89 (s, 1H), 6.52 (dd, J=8.9, 2.4 Hz, 1H), 6.92 (d, J=8.3 Hz, 2H), 7.29 (d, J=8.1 Hz, 2H), 7.60 (d, J=8.9 Hz, 1H); Anal. Calc'd for C₃₀H₄₅NO₇S₂: C, 60.48; H, 7.61; N, 2.35. Found: C, 60.53; H, 7.70; N, 2.42.

Step 2: Preparation of 7-(dimethylamino)-benzothiepin-5-yl]phenoxy-1-butanesulfonamide

To a solution of 1.12 g (1.88 mmol) of the sulfonic acid (obtained from Step 1) in 10 mL CH₂Cl₂ was added 785 mg (3.77 mmol) PCl₅ and stirred for 1 hour. Water was added and the mixture was extracted and washed with brine. Dried with MgSO₄, filtered and solvent evaporated. To the residue was added 30 mL of 0.5 M NH₃ in dioxane and stirred 16 hours. The precipitate was filtered and the solvent evaporated. The residue was purified by MPLC (33% EtOAc in hexane) to afford the desired title compound as a beige solid (125 mg, 11%): mp 108-110° C.; ¹H NMR (CDCl₃) δ0.85-0.93 (m, 6H), 1.13-1.59 (m, 10H), 1.60-1.67 (m, 1H), 1.94-2.20 (m, 5H), 2.82 (s, 6H), 2.99 (d, J=15.3 Hz, 1H), 3.15 (t, J=15.3 Hz, 1H), 3.23 (t, J=7.7 Hz, 2H), 4.03 (t, J=5.8 Hz, 2H), 4.08-4.10 (m, 1H), 4.79 (s, 2H), 5.47 (s, 1H), 6.02 (d, J=2.4 Hz, 1H), 6.52 (dd, J=8.9, 2.6 Hz, 1H), 6.91 (d, J=8.9 Hz, 2H), 7.41 (d, J=8.5 Hz, 2H), 7.89 (d, J=8.9 Hz, 1H). HRMS. Calc'd for C₃₀H₄₇N₂O₆S₂: 595.2876. Found: 595.2874.

Example 1406

(4R-cis)-1-[3-[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]propyl]-4-aza-1-azoniabicyclo[2.2.2]octane, methanesulfonate (salt)

Step 1: Preparation of Dimesylate Intermediate

To a cooled (−20° C.) solution of 5.0 g (65.7 mmol) of 1,3-propanediol in 50 mL of triethylamine and 200 mL of methylene chloride was added 15.8 g (137.9 mmol) of methanesulfonyl chloride. The mixture was stirred for 30 minutes, then warmed to ambient temperature and partitioned between ethyl acetate and 1N HCl. The organic layer was washed with brine, dried over MgSO₄, and concentrated in vacuo to give 13.5 g (89%) of dimesylate intermediate as a clear yellowish oil: ¹H NMR (CDCl₃) δ2.12 (quintet, J=4.5 Hz, 4H), 3.58 (s, 6H), 4.38 (t, J=5.4 Hz)

Step 2: Preparation of Propyl Mesylate Intermediate

To a solution of 2.4 g (5.2 mmol) of 5-(4′-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzothiepine-1-dioxide (obtained from Example 1402, Step 10) and 6.0 g (26.1 mmol) of dimesylate intermediate (obtained from Step 1) in 50 mL of acetone was added 3.6 g (26.1 mmol) of K₂CO₃. The reaction was heated to reflux overnight then cooled to ambient temperature and concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over MgSO₄, and concentrated in vacuo. Purification by silica gel chromatography (Waters-Prep 500) using 36% ethyl acetate/hexanes afforded 2.8 g (90%) of the propyl mesylate intermediate as a white foam: ¹H NMR (CDCl₃) δ0.86-0.95 (m, 6H), 1.06-1.52 (m, 10H), 1.57-1.70 (m, 1H), 2.14-2.32 (m, 3H), 2.84 (s, 6H), 3.02 (s, 3H), 3.08 AB_(q), J_(AB)=15.0 Hz, J=46.9 Hz, 4.09-4.18 (m, 3H) , 4.48 (t, J=6.0 Hz, 2H), 5.49 (s, 1H), 6.11 (s, 1H) , 6.65 (d, J=8.7 Hz, 1H), 6.94(d, J=8.6 Hz, 2H), 7.43 (d, J=8.5 Hz, 2H) , 7.94 (d, J=8.9 Hz, 1H).

Step 3: Preparation of Quaternary Salt

To a solution of 1.2 g (2.0 mmol) of propyl mesylate intermediate (obtained from Step 2) in 20 ml of acetonitrile was added 0.3 g (2.9 mmol) of 1,4-diazabicyclo[2.2.2]octane (DABCO). The reaction mixture was stirred at 60° C. for three hours, then cooled to ambient temperature and concentrated in vacuo. Purification by trituration with methylene chloride/ethyl ether gave 1.3 g (91%) of the desired title compound as a white solid: mp. (dec) 230-235° C.; ¹H NMR (CDCl₃) δ0.86-0.95 (m, 6H), 1.04-1.52 (m, 10H), 1.57-1.70 (m, 1H), 2.12-2.25 (m, 3H), 2.28-2.39 (m, 2H), 2.83 (s, 6H), 3.04 (s, 3H), 3.09 (AB_(q), J_(AB)=15.6 Hz, J=42.2 Hz, 2H) 3.22-3.32 (m, 6H), 3.56-3.66 (m, 6H), 3.73-3.83 (m, 2H), 4.06-4.17 9m, 3H), 5.47 (s, 1H), 5.97 (s, 1H), 6.51 (d, J=8.6 Hz, 1H), 6.90(d, J=8.6 Hz, 2H), 7.41 (d, J=8.7 Hz, 2H), 7.89 (d, J=8.9 Hz, 1H). MS (ES+) m/e 612.4. HRMS (ES+) Calc'd for C₃₅H₅₄N₃O⁴S⁺: 612.3835. Found: 612.3840.

Example 1407

(4R-cis)-1-[3-[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]propyl]-4-aza-1-azoniabicyclo[2.2.2]octane,4-methylbenzenesulfonate (salt)

Step 1: Preparation of Propyl Tosylate Intermediate

A solution of 5-(4′-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzothiepine-1,1-dioxide (5.0 g, 10.9 mmol, obtained from Example 1402, Step 10) in acetone (100 mL) at 25° C. under N₂ was treated with powdered K₂CO₃ (3.8 g, 27.2 mmol, 2.5 eq.) and 1,3-propanediol di-p-tosylate (13.0 g, 32.6 mmol, 3.0 eq.), and the resulting mixture was stirred at 65° C. for 21 hours. The cream-colored slurry was cooled to 25° C. and was filtered through a sintered glass funnel. The filtrate was concentrated and the residue was dissolved in EtOAc (150 mL). The organic layer was washed with saturated aqueous NaHCO₃ (2×150 mL) and saturated aqueous NaCl (2×150 mL), and was dried (MgSO₄) and concentrated in vacuo to provide a pale orange oil. Purification by flash chromatography (4.4×35 cm silica, 20-30% EtOAc/hexane) afforded the propyl tosylate intermediate (6.0 g, 80%) as a white foam: ¹H NMR (CDCl₃) δ0.91 (m, 6H), 1.11-1.47 (br m, 10H), 1.63 (m, 1H), 2.14 (m, 2H), 2.21 (m, 1H), 2.41 (s, 3H), 2.81 (s, 6H), 3.06 (ABq, J=15.1 Hz, J=49.0 Hz, 2H), 4.01 (t, J=5.3 Hz, 2H), 4.10 (m, 1H), 4.26 (t, J=5.9 Hz, 2H), 5.29 (s, 1H), 5.48 (s, 1H), 5.98 (s, 1H), 6.51 (dd, J=8.9, 1.8 Hz, 1H), 6.83 (d, J=8.4 Hz, 2H), 7.30 (d, J=8.1 Hz, 2H), 7.39 (d, J=8.3 Hz, 2H), 7.78 (d, J=8.3 Hz, 2H), 7.88 (d, J=8.9 Hz, 1H).

Step 2: Preparation of Quaternary Salt

A solution of the propyl tosylate intermediate (1.05 g, 1.56 mmol, obtained from Step 1) in acetonitrile (15 mL) at 25° C. under N₂ was treated with diazabicyclo[2.2.2]octane (DABCO, 0.26 g, 2.34 mmol, 1.5 eq.) and stirred at 50° C. for 6 hours, then at 25° C. for 14 hours. The pale amber solution was cooled to 25° C. and concentrated in vacuo to provide an amber oil. The residue was dissolved in a minimal amount of CH₂Cl₂ (5 mL) and diluted with Et₂O (100 mL) while vigorously stirring for 4 hours, during which time a white solid precipitated. The white solid was collected (Et₂O wash) to give the desired title compound (1.11 g, 90%) as a white amorphous solid: mp 136.5-142° C. (decomposed); ¹H NMR (CDCl₃) δ0.89 (m, 6H), 1.12-1.43 (br m, 9H), 1.61 (m, 1H), 1.65 (m, 1H), 2.18 (m, 1H), 2.22 (m, 2H), 2.27 (s, 3H), 2.78 (s, 6H), 3.07 (ABq, J=15.1 Hz, J=39.5 Hz, 2H), 3.49 (br s, 6H), 3.68 (m, 1H), 3.74 (br s, 6H), 3.96 (br s, 2H), 4.09 (d, J=7.3 Hz, 1H), 5.46 (s, 1H), 5.96 (d, J=2.4 Hz, 1H), 6.49 (dd, J=8.9, 2.4 Hz, 1H), 6.83 (d, J=8.5 Hz, 2H), 7.11 (d, J=8.1 Hz, 2H), 7.40 (d, J=8.3 Hz, 2H), 7.74 (d, J=8.1 Hz, 2H), 7.87 (d, J=8.9 Hz, 1H); HRMS. Calc'd for C₃₅H₅₄N₃O₄S: 612.3835. Found: 612.3832.

Example 1408

(4R-cis)-1-[4-[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl ]phenoxy]butyl]-4-aza-1-azoniabicyclo[2.2.2]octanemethanesulfonate (salt)

Step 1: Preparation of Butyl Mesylate Intermediate

A mixture of 1.00 g (2.18 mmol) of 5-(4′-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzothiepine-1,1-dioxide (obtained from Example 1402, Step 10), 2.68 g (10.88 mmol) of busulfan, and 1.50 g (10.88 mmol) of potassium carbonate in 20 mL of acetone was stirred at reflux overnight. The mixture was concentrated in vacuo and the crude was dissolved in 30 mL of ethyl acetate. The insoluble solid was filtered off and the filtrate was concentrated in vacuo. The resulting white foam was chromatographed through silica gel column, and eluted with 30% ethyl acetate/hexane to give 1.02 g (77%) of butyl mesylate intermediate as a white solid: ¹H NMR (CDCl₃) δ0.90 (m, 6H), 1.20-1.67 (m, 12H), 1.98 (m, 4H), 2.22 (m, 1H), 2.83 (s, 6H), 3.04 (s, 3H), 3.08 (ABq, 2H), 4.05 (t, J=5.55 Hz, 2H), 4.11 (d, J=6.90 Hz, 1H), 4.35 (t, J=6.0 Hz, 2H), 5.49 (s, 1H), 6.00 (d, J=2.4 Hz, 1H), 6.52 (dd, J=9.0 Hz, 2.7 Hz, 1H), 6.93 (d, J=9.0 Hz, 2H), 7.42 (d, J=8.4 Hz, 2H), 7.90 (d, J=9.0 Hz, 1H).

Step 2: Preparation of Ester Intermediate

A solution of 520 mg (0.85 mmol) of butyl mesylate intermediate (obtained from Step 1) and 191 mg (1.71 mmol) of DABCO in 10 mL of acetonitrile was stirred at 80° C. for 4 hours. The reaction mixture was concentrated in vacuo to yield a white foam. The foam was crushed and washed with ether. The solid was filtered off and dried in vacuo to give 540 mg (88%) of the desired title compound which was recrystallized from methylene chloride and acetone as a white solid: mp 248-251° C.; ¹H NMR (CDCl₃) δ0.91 (m, 6H), 1.14-1.47 (m, 14H), 1.63 (m, 1H), 1.96 (m, 4H), 2.21 (m, 1H), 2.77 (s, 3H), 2.82 (s, 3H), 3.07 (ABq, 2H), 3.26 (t, J=7.1 Hz, 6H), 3.60 (m, 8H), 4.08 (m, 3H), 5.47 (s, 1H), 5.99 (d, J=2.4 Hz, 1H), 6.51 (dd, J=8.9 Hz, 2.6 Hz, 1H), 6.91 (d, J=8.7 Hz, 2H), 7.41 (d, J=8.1 Hz, 2H), 7.89 (d, J=9.0 Hz, 1H).

Example 1409

(4R-cis)-1-[4-[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]butyl]-4-aza-1-azoniabicyclo[2.2.2]octane-4-methylbenzenesulfonate (salt)

Step 1: Preparation of Propyl Tosylate Intermediate

A solution of 5-(4′-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzothiepine-1,1-dioxide (5.0 g, 10.9 mmol, obtained from Example 1402, Step 10) in acetone (100 mL) at 25° C. under N₂ was treated with powdered K₂CO₃ (3.8 g, 27.2 mmol, 2.5 eq.) and 1,4-butanediol di-p-tosylate (13.0 g, 32.6 mmol, 3.0 eq.), and the resulting solution was stirred at 65° C. for 21 hours. The cream-colored slurry was cooled to 25° C. and filtered through a sintered glass funnel. The filtrate was concentrated and the residue was dissolved in EtOAc (150 mL). The organic layer was washed with saturated aqueous NaHCO₃ (2×150 mL) and saturated aqueous NaCl (2×150 mL). The extract was dried (MgSO₄) and concentrated in vacuo to provide a pale orange oil. Purification by flash chromatography (4.4×35 cm silica, 20-30% EtOAc/hexane) afforded the propyl tosylate intermediate (6.0 g, 80%) as a white foam: ¹H NMR (CDCl₃) δ0.89 (m, 6H), 1.10-1.44 (br m, 10H), 1.61 (m, 1H), 1.84 (m, 4H), 2.19 (m, 1H), 2.43 (s, 3H), 2.80 (s, 6H), 3.03 (ABq, J=15.1 Hz, J=46.3 Hz, 2H), 3.93 (m, 2H), 4.06-4.13 (m, 4H), 5.44 (s, 1H), 5.96 (s, 1H), 6.46 (dd, J=8.9, 1.4 Hz, 1H), 6.85 (d, J=8.1 Hz, 2H), 7.33 (d, J=8.1 Hz, 2H), 7.38 (d, J=8.1 Hz, 2H), 7.78 (d, J=8.9 Hz, 2H), 7.83 (m, 1H).

Step 2: Preparation of Quaternary Salt

A solution of propyl tosylate intermediate (5.8 g, 8.5 mmol, obtained from Step 1) in acetonitrile (100 mL) at 25° C. under N₂ was treated with diazabicyclo[2.2.2]octane (DABCO, 1.1 g, 10.1 mmol, 1.2 eq.) and stirred at 45° C. for 6 hours. The pale yellow solution was cooled to 25° C. and concentrated in vacuo to provide an off-white solid. The residue was dissolved in a minimal amount of CH₂Cl₂ (5 mL) and diluted with Et₂O (100 mL) while vigorously stirring for 3 hours, during which time a white solid precipitated. The white solid was collected and recrystallized from EtOAc/hexane to give the desired title compound (5.7 g, 85%) as colorless needles: mp 223-231° C. (decomposed); ¹H NMR (CDCl₃) δ0.86 (m, 6H), 1.09-1.43 (br m, 12H), 1.61-1.90 (br m, 5H), 2.13 (m, 1H), 2.25 (s, 3H), 2.75 (s, 6H), 3.03 (ABq, J=15.1 Hz, J=30.0 Hz, 2H), 3.05 (br s, 6H), 3.37 (br s, 6H), 3.89 (m, 2H), 4.07 (d, J=7.5 Hz, 1H), 5.39 (s, 2H), 5.97 (d, J=1.6 Hz, 1H), 6.44 (dd, J=8.9, 2.0 Hz, 1H), 6.87 (d, J=8.3 Hz, 2H), 7.08 (d, J=8.1 Hz, 2H), 7.37 (d, J=8.3 Hz, 2H), 7.71 (d, J=8.1 Hz, 2H), 7.80 (d, J=8.9 Hz, 1H); HRMS. Calc'd for C₃₆H₅₆N₃O₄S: 626.3992. Found: 626.3994. Anal. Calc'd for C₄₃H₆₃N₃O₇S₂: C, 64.71; H, 7.96; N, 5.27. Found: C, 64.36; H, 8.10; N, 5.32.

Example 1410

(4R-cis)-4-[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]-N,N,N-triethyl-1-butanaminium

A solution of 1 g (1.64 mmol) of the butyl mesylate intermediate (obtained from Example 1408, Step 1) and 15 mL of triethylamine in 10 mL of acetonitrile was heated at 50° C. for 2 days. The solvent was evaporated and the residue was triturated with ether and ethyl acetate to afford 500 mg (43%) of product as a semi-solid. ¹H NMR (CDCl₃) δ0.8 (m, 6 H), 1-1.6 (m, 24 H), 2.1 (m, 1 H), 2.6 (s, 3 H), 2.7 (s, 6 H), 2.9 (d, J=15 Hz, 1 H), 3.0 (d, J=15 Hz, 1 H), 3.3 (m, 8 H), 4.0 (m, 4 H), 5.3 (s, 1 H), 5.9 (s, 1 H), 6.4 (m, 1 H), 6.8 (d, J=9 Hz, 2 H), 7.4 (d, J=9 Hz, 2 H), 7.8 (d, J=7 Hz, 1 H). MS m/e 615.

Example 1411

(4R-cis)-1-[4-[4-[3,3-Dibutyl-7-(dinmethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]butyl]-3-hydroxypyridinium, methanesulfonate (salt)

A solution of 1 g (1.64 mmol) of the butyl mesylate intermediate (obtained from Example 1408, Step 1) and 234 mg (2.46 mmol) of 3-hydroxy pyridine in 1 mL of dimethylformamide was heated at 70° C. for 20 hours. The solvent was evaporated and the residue was triturated with ether and ethyl acetate to afford 990 mg (86%) of product as a semi-solid: ¹H NMR (CDCl₃) δ0.9 (m, 6 H), 1-1.5 (m, 10 H), 1.7 (m, 1 H), 1.9 (m, 2 H), 2-2.4 (m, 3 H), 2.9 (s, 6 H), 3.1 (d, J=15 Hz, 1 H), 3.2 (d, J=15 Hz, 1 H), 4.1 (m, 3 H), 4.7 (m, 2 H), 5.5 (s, 1 H), 6.1 (s, 1 H), 6.6 (m, 1 H), 6.9 (d, J=9 Hz, 2 H), 7.4 (d, J=9 Hz, 2 H), 7.7 (m, 1 H), 8.0 (m, 2 H), 8.2 (m, 1 H), 9.1 (s, 1 H). MS m/e 609.

Example 1412

(4R-cis)-1-[5-[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl ]phenoxy]pentyl]quinolinium, methanesulfonate (salt)

Step 1: Preparation of Pentyl Mesylate Intermediate

To a stirred solution of 231 mg (5.79 mmol, 60% disp.) of NaH in 22 mL of DMF was added 2.05 g (4.45 mmol) of 5-(4′-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzothiepine-1,1-dioxide (obtained from Example 1402, Step 10), and the resulting solution was stirred at ambient temperature for 1 hour. To the mixture was added 18.02 g (55.63 mmol) of 1,5-dibromopentane and the solution was stirred overnight at ambient temperature. DMF was removed by high vacuum and the residue was extracted with ethyl acetate and washed with brine. The extract was dried over MgSO₄, and the concentrated residue was purified by column chromatography to give the pentyl mesylate intermediate: ¹H NMR (CDCl₃) δ0.90(q, 6H), 1.05-2.0 (m, 17H), 2.2 (t, 1H), 2.8 (s, 6h), 3.0 (q, 2H), 3.22 (t, 2H), 3.95 (t, 2H), 4.1 (s, 1H), 5.42 (s, 1H), 6.1 (d, 1H), 6.6 (d, 1H), 6.9 (d, 2H), 7.4 (d, 2H), 7.9 (d, 1H).

Step 2: Preparation of Quaternary Salt

To 1.0 g (1.53 mmol) of the pentyl mesylate intermediate (obtained from Step 1) was added 3.94 g (30.5 mmol) of quinoline and 30 mL of acetonitrile. The solution was heated at 45° C. under N₂ for 10 days. The concentrated residue was purified by reverse phase C18 column chromatography. The obtained material was exchanged to its mesylate anion by ion exchange chromatography to give the desired title compound as a solid: mp 136° C.; ¹H NMR (CDCl₃) δ0.95(q, 6H), 1.05-2.25 (m, 18H), 2.8 (s, 9H), 3.0 (q, 2H), 3.95 (t, 2H), 4.1 (s, 1H), 5.28 (t, 2H), 5.42 (s, 1H), 5.95 (s, 1H), 6.45 (d, 1H), 6.82 (d, 2H), 7.4 (d, 2H), 7.82 (d, 1H), 7.9 (t, 1H), 8.2 (t, 2H), 8.3 (q, 2H), 8.98 (d, 1H), 10.2 (d, 1H). HRMS. Calc'd for C₄₀H₅₃N₂O₄S: 657.3726. Found: 657.3736. Anal. Calc'd for C₄₀H₅₃N₂O₄S.CH₃O₃S: C, 65.40; H, 7.50; N, 3.72; S, 8.52. Found: C, 62.9; H, 7.42; N, 3.56; S, 8.41.

Example 1413

(4S-cis)-[5-[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]pentyl]propanedioic acid

Step 1: Preparation of Pentyl Bromide Intermediate

To a stirred solution of 0.63 g (15.72 mmol, 60% disp) of NaH in 85 mL of DMF was added 6.0 g (13.1 mmol) of 5-(4′-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzothiepine-1,1-dioxide (obtained from Example 1402, Step 10), and the resulting solution was stirred at ambient temperature for 1 hour. To the solution was added 37.7 g (163 ,75 mmol) of 1,5-dibromopentane, and the mixture was stirred overnight at ambient temperature. DMF was removed in vacuo and the residue was extracted with ethyl acetate and washed with brine. The extract was dried over MgSO₄, and the concentrated residue was purified by column chromatography to give the pentyl bromide intermediate: ¹H NMR (CDCl3) δ0.90 (q, 6H), 1.05-2.0 (m, 17H), 2.2 (t, 1H), 2.8 (s, 6H), 3.0 (q, 2H), 3.4 (t, 2H), 3.95 (t, 2H), 4.1 (s, 1H), 5.42 (s, 1H), 6.0 (s, 1H), 6.5 (d, 1H), 6.9 (d, 2H), 7.4 (d, 2H), 7.9 (d, 1H).

Step 2: Preparation of Dibenzyl Ester Intermediate

To the mixture of 59 mg (1.476 mmol, 60% disp) of NaH in 27 mL of THF and 9 mL of DMF at 0° C. was added 0.84 g (2.952 mmol) of dibenzyl malonate (Aldrich), and the resulting solution was stirred at ambient temperature for 15 min. To the solution was added 0.5987 g (0.984 mmol) of the pentyl bromide intermediate, and the mixture was stirred at 80° C. overnight. Solvent was removed in vacuo, and the residue was extracted with methylene chloride and washed with brine. The extract was dried over MgSO₄, and the concentrated residue was purified by column chromatography to give the dibenzyl ester intermediate: ¹H NMR (CDCl₃) δ0.90 (q, 6H), 1.05-2.0 (m, 19H), 2.2 (t, 1H), 2.8 (s, 6H), 3.0 (q, 2H), 3.4 (t, 1H), 3.9 (t, 2H), 4.1 (d, 1H), 5.18 (s, 4H), 5.42 (s, 1H), 5.95 (s, 1H), 6.5 (d, 1H), 6.9 (d, 2H), 7.2-7.4 (m, 12H), 7.85 (d, 1H).

Step 3: Preparation of Diacid

A suspension of 0.539 g (0.664 mmol) of the dibenzyl ester intermediate (obtained from Step 2) and 25 mg of 10% Pd/C in 30 mL of ethanol was agitated at ambient temperature under 20 psi of hydrogen gas for 2 hours. The catalyst was filtered off, and the filtrate was concentrated to give the desired title compound as a solid: mp 118° C.; ¹H NMR (CDCl₃) δ0.9 (d, 6H), 1.05-2.2 (m, 20H), 2.8 (s, 6H), 3.0 (q, 2H), 3.4 (s, 1H), 3.95 (s, 2H), 4.1 (s, 1H), 5.42 (s, 1H), 5.95 (s, 1H), 6.5 (d, 1H), 6.9 (d, 2H), 7.4 (d, 2H), 7.85 (d, 1H). HRMS. Calc'd for C₃₄H₄₉NO₈S: 632.3257. Found: 632.3264. Anal. Calc'd for C₃₄H₄₉NO₈S: C, 64.63; H, 7.82; N, 2.22; S, 5.08. Found: C, 63.82; H, 7.89; N, 2.14; S, 4.93.

Example 1414

(4R-cis)-3,3-Dibutyl-5-[4-[[5-(diethylamino)pentyl]oxy]phenyl]-7-(dimethylamino)-2,3,4, 5-tetrahydro-1-benzothiepin-4-ol 1,1-dioxide

Step 1: Preparation of Pentyl Iodide Intermediate

To a solution of 5-(4′-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzothiepine-1,1-dioxide (3 g, 6.53 mmol, obtained from Example 1402, Step 10) in 100 mL of dimethylformamide was added 198 mg (7.83 mmol) of 95% sodium hydride. The mixture was stirred 15 minutes at room temperature and diiodopentane was added. After one hour at room temperature the mixture was diluted in ethyl acetate and water. The aqueous layer was extracted with ethyl acetate and the combined organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was chromatographed over silica gel, eluting with hexane/ethyl acetate (1/5) to afford 2.92 g (4.46 mmol) of the pentyl iodide intermediate: ¹H NMR (CDCl₃) δ0.9 (m, 6 H), 1-1.5 (m, 11 H), 1.6 (m, 3 H), 1.8 (m, 4 H), 2.2 (m, 1 H), 2.8 (s, 6 H), 3.0 (d, J=15 Hz, 1 H), 3.2 (d, J=15 Hz, 1 H), 3.3 (m, 2 H), 4.0 (m, 1 H), 4.1 (s, 1 H), 5.5 (s, 1 H), 6.1 (s, 1 H), 6.6 (m, 1 H), 6.9 (d, J=9 Hz, 2 H), 7.4 (d, J=9 Hz, 2 H), 7.9 (d, J=7 Hz, 1 H).

Step 2: Preparation of Amine

A solution of 550 mg (0.76 mmol) of the pentyl iodide intermediate (obtained from Step 1) and 279 mg (3.81 mmol) of diethylamine in 3 mL of acetonitrile was stirred at 100° C. overnight. The mixture was concentrated in vacuo to yield a yellowish brown foam. The foam was dissolved in 10 mL of ethyl acetate and washed with 50 mL of saturated sodium carbonate solution twice. The ethyl acetate layer was dried over magnesium sulfate and concentrated to yield 390 mg (85%) of the desired title compound as a yellow foamy solid: ¹H NMR (CDCl₃) δ0.89 (m, 6H), 1.20-1.47 (m, 12H), 1.53-1.67 (m, 4H), 1.76-1.90 (m, 8H), 2.21 (m, 1H), 2.74-2.92 (m, 12H), 3.07 (ABq, 2H), 4.00 (t, J=6.3 Hz, 2H), 4.10 (d, J=7.8 Hz, 1H), 5.48 (s, 1H), 6.00 (d, J=2.4 Hz, 1H), 6.51 (dd, J=9.2 Hz, 2.6 Hz, 1H), 6.92 (d, J=8.7 Hz, 2H), 7.41 (d, J=8.4 Hz, 2H), 7.90 (d, J=9.0 Hz, 1H).

Example 1415

(4R-cis)-N-(Carboxymethyl)-N-[5-[4-[3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]pentyl]glycine

Step 1: Preparation of Diester Intermediate

A mixture of 8.6 g (14.1 mmol) of pentyl bromide intermediate (obtained from Example 1413, Step 1), 65 g (0.35 mol) of diethylaminodiacetate and 7.5 g (71 mmol) of anhydrous Na₂CO₃ was stirred at 160° C. for 3 hours. The reaction mixture was diluted with water and extracted with methylene chloride. The volatiles was removed in vacuo to give 9.6 g (95%) of the diester intermediate. ¹H NMR spectrum was consistent with the structure; MS (M+H) m/e 717.

Step 2: Preparation of Diacid

The mixture of the diester intermediate (obtained from Step 1) and 2.7 g (64.3 mmol) of LiOH in THF (75 mL) and water (50 mL) was stirred at 40° C. for 18 hours. The reaction mixture was acidified with 1% HCl and extracted with dichloromethane. The residue was triturated with hexane, filtered to give 8.9 g (93%) of the desired title compound as a solid: mp 148-162° C.; ¹H NMR (CD₃OD) δ0.92 (t, 6H), 1.1-1.9 (m, 31H), 2.15 (t, 1H),2.8(s, 6H), 3.15 (ABq, 2H), 3.75(m, 1H), 4.1 (m, 6H), 5.3(s, 1H), 6.1 (s, 1H), 6.6 (d, 1H), 7.0(d, 2H), 7.4 (d, 2H), 7.8 (d, 1H); MS (M+H) m/e 661. Anal. Calc'd for [C₃₅H₅₂N₂O₈S +1.5H₂O]: C,61.11; H,8.06; N,4.07; S,4.66. Found: C,61.00; H,7.72; N,3.89; S,4.47.

Example 1416

(4R-cis)-5-[4-[[5-[bis[2-(Diethylamino) ethyl]amino]pentyl]oxy]phenyl]-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-1-benzothiepin-4-ol 1,1-dioxide

A solution of 1 g of pentyl iodide intermediate (1.53 mmol, obtained from Example 1414, Step 1) in N,N,N′,N′-tetraethyl diethylenetriamine was heated to 80° C. for 4 hours. The mixture was dissolved in ethyl acetate and saturated NaHCO₃. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by reverse phase chromatography. The fractions containing the product were concentrated in vacuo, dissolved in ethyl acetate and washed with saturated NaHCO₃. The residue was dried and concentrated in vacuo to afford 840 mg (74%) of the desired title compound as a thick oil. ¹H NMR (CDCl₃) δ0.8 (m, 6 H), 1-1.6 (m, 28 H), 1.8 (m, 2 H), 2.1 (m, 1 H), 2.5 (m, 18 H), 2.7 (s, 6 H), 2.9 (d, J=15 Hz, 1 H), 3.1 (d, J=15 Hz, 1 H), 3.9 (m, 2 H), 4.0 (m, 1 H), 4.1 (s, 1 H), 5.4 (s, 1 H), 6.0 (s, 1 H), 6.4 (m, 1 H), 6.9 (d, J=9 Hz, 2 H), 7.4 (d, J=9 Hz, 2 H), 7.8 (d, J=7 Hz, 1 H). MS (M+H) m/e 743.

Example 1417

(4R-cis)-3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-[4-[[5-[2-(1H-imidazol-4-yl)ethyl]amino]pentyl]oxy]phenyl]-1-benzothiepin-4-ol 1,1-dioxide

A solution of 1 g of pentyl iodide intermediate (1.53 mmol, obtained from Example 1414, Step 1) and 3.4 g (30.6 mmol) of histamine was heated to 50° C. for 17 hours. The mixture was dissolved in ethyl acetate and saturated NaHCO₃. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was triturated with ether to afford 588 mg (60%) of the desired title compound as a semi-solid: ¹H NMR (CDCl₃) δ0.9 (m, 6 H), 1-1.7 (m, 14 H), 1.9 (m, 3 H), 2.0 (m, 2 H), 2.2 (m, 1 H), 2.8 (s, 6 H), 3.0 (m, 3 H), 3.2 (m, 2 H), 4.0 (m, 2 H), 4.1 (m, 3 H), 5.5 (s, 1 H), 6.0 (s, 1 H), 6.5 (m, 1 H), 6.8 (s, 1 H), 6.9 (d, J=9 Hz, 2 H), 7.4 (m, 3 H), 7.9 (d, J=8 Hz, 1 H). MS (M+H) m/e 639.

Example 1418

(4R-cis)-N-[5-[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl ]phenoxy]pentyl]-N′-ethyl-N,N,N′,N′-tetramethyl-1,2-ethanediaminium dichloride

Step 1: Preparation of Pentyl Bromide Intermediate

A mixture of 5-(4′-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzothiepine-1,1-dioxide (1.680 g, 3.66 mmol, obtained from Example 1402, Step 10) and sodium hydride (0.250 g, 6.25 mmol) in 30 mL of DMF was stirred in a dry 100 mL round-bottom flask under N₂. To this solution was added 1,5-dibromopentane (6.0 mL/44.0 mmol), and the resulting mixture was stirred for 18 hours. The reaction was diluted with brine (100 mL) and H₂O (20 mL), and the mixture was extracted with EtOAc (3×50 mL). Organic layers were combined, dried (MgSO₄), filtered and concentrated in vacuo. Purification by filtration through silica gel eluting with 20% EtOAc/hexane and evaporation in vacuo gave pentyl bromide intermediate as a white foamy solid (1.783 g, 80%): ¹H NMR (CDCl₃) δ0.84-0.95 (m, 6H), 1.02-1.56 (m, 10H), 1.58-1.70 (m, 3H), 1.78-2.03 (m, 4H), 2.15-2.24 (m, 1H), 2.77 (s, 1H), 2.80 (s, 6H), 3.05 (ABq, 2H), 3.42 (t, 2H), 3.98 (t, 2H), 4.10 (s, 1H), 5.47 (s, 1H), 5.99 (d, 1H), 6.50 (dd, 1H), 6.91 (d, 2H), 7.40 (d, 2H), 7.88 (d, 1H).

Step 2: Preparation of Mono-quaternary Salt

The mixture of pentyl bromide intermediate (0.853 g, 1.40 mmol, obtained from Step 1), N,N,N′,N′-tetramethylethylenediamine (1.0 mL/6.62 mmol) in 30 mL of acetonitrile was stirred at 40° C. for 12 hours, and the reaction mixture was concentrated in vacuo to give an off-white foamy solid (1.052 g). The crude product was dissolved in acetonitrile (1.5 mL) and triturated with ethyl ether. The solvent was decanted to yield a sticky solid. This trituration method was repeated twice, and the resulting sticky solid was concentrated in vacuo to give the mono-quaternary salt as an off-white foamy solid (0.951 g, 94%): ¹H NMR (CDCl₃) δ0.81 (t, 6H), 0.96-1.64 (m, 13H), 1.62-1.85 (m, 4H), 2.03-2.18 (m, 1H), 2.20 (s, 6H), 2.67 (t, 2H), 2.74 (s, 6H), 2.98 (ABq, 2H), 3.30-3.42 (m, 1H), 3.38 (s, 6H), 3.60-3.75 (m, 4H), 3.90 (t, 2H), 4.01 (s, 1H), 5.37 (s, 1H), 5.92 (s, 1H), 6.41 (dd, 1H), 6.81 (d, 2H), 7.32 (d, 2H), 7.77 (d, 1H).

Step 3: Preparation of Di-quaternary Salt

The mono-quaternary salt (0.933 g, 1.29 mmol, obtained from Step 2), iodoethane (0.300 mL/3.75 mmol), and acetonitrile (30.0 mL) were combined in a 4 oz. Fischer Porter bottle. The reaction vessel was purged with N₂, sealed, equipped with magnetic stirrer, and heated to 50° C. After 24 hours, the reaction mixture was cooled to ambient temperature and concentrated in vacuo to give a yellow foamy solid (1.166 g). The solid was dissolved in methylene chloride/acetonitrile and precipitated with ethyl ether. After cooling to 0° C. overnight, the resulting solid was filtered, washed with ethyl ether and concentrated in vacuo to yield the di-quaternary salt as an off-white solid (1.046 g, 92%): ¹H NMR (CD₃OD) δ0.59 (t, 6H), 0.70-1.10 (m, 9H), 1.16 (t, 3H), 1.22-1.80 (m, 9H), 2.42 (s, 6H), 2.78 (d, 2H), 2.98 (s, 6H), 3.02 (s, 6H), 3.22-3.37 (m, 4H), 3.63-3.78 (m, 4H), 3.80 (s, 4H), 4.93 (s, 1H), 5.71 (s, 1H), 6.22 (dd, 1H), 6.61 (d, 2H), 7.02 (d, 2H), 7.40 (d, 1H).

Step 4: Preparation of Quaternary Di-chloride Salt

The iodobromosalt (obtained from Step 3) was converted to its corresponding dichloride salt using Biorad AG 2×8 resin and eluting with 70% H₂O/acetonitrile to give the desired title compound as a white foamy solid (0.746 g, 84%): mp 193.0-197.0° C.; ¹H NMR (CD₃OD) δ0.59 (t, J=6.0 Hz, 6H), 0.70-1.12 (m, 9H), 1.16 (t, J=6.6 Hz, 3H), 1.24-1.90 (m, 9H), 2.50 (s, 6H), 2.78 (s, 2H), 3.08 (s, 6H), 3.11 (s, 6H), 3.24-3.50 (m, 4H), 3.68 (s, 2H), 3.81 (s, 2H), 4.16 (s, 4H), 5.02 (s, 1H), 5.72 (s, 1H), 6.19 (d, J=8.4 Hz, 1H), 6.61 (d, J=8.1 Hz, 2H), 7.10 (d, J=7.8 Hz, 2H), 7.46 (d, J=8.7 Hz, 1H). HRMS. Calc'd for C₃₉H₆₇N₃O₄SCl: 708.4541. Found: 708.4598.

Example 1419

[4R-[4a,5a(4R*,5R*)]]-N,N′-bis[5-[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]pentyl]-N,N,N′N′-tetramethyl-1,6-hexanediaminium dichloride

The pentyl bromide intermediate (1.002 g, 1.64 mmol, obtained from Example 1418, Step 1) and N,N,N′,N′-tetramethyl-1,6-hexanediamine (0.100 g, 0.580 mmol) in 5 mL of acetonitrile were placed in a 4 oz. Fischer Porter bottle. The reaction vessel was purged with N₂, sealed, equipped with magnetic stirrer and heated to 50° C. After 15 hours, the reaction mixture was cooled to ambient temperature and concentrated in vacuo to give an off-white foamy solid (1.141 g). The solid was dissolved in acetonitrile and precipitated with ethyl ether. After cooling to 0° C., the solvent was decanted to yield a sticky off-white solid. This trituration method was repeated, and the resulting sticky solid was concentrated in vacuo to give the desired dibromide salt as an off-white foamy solid (0.843 g, quantitative): ¹H NMR (CDCl₃) δ0.85 (m, 12H), 1.01-1.70 (m, 30H), 1.76-2.08 (m, 12H), 2.18 (t, J=12.3 Hz, 2H), 2.79 (s, 12H), 3.03 (ABq, 4H), 3.35 (s, 12H), 3.52 (br s, 6H), 3.72 (br s, 4H), 3.97 (br s, 4H), 4.08 (br s, 2H), 5.42 (s, 2H), 6.00 (s, 2H), 6.51 (d, J=9.0 Hz, 2H), 6.86 (d, J=7.8 Hz, 4H), 7.38 (d, J=7.8 Hz, 4H), 7.83 (d, J=8.7 Hz, 2H). The dibromide salt was converted to its corresponding dichloride salt using Biorad AG 2×8 resin and eluting with 70% H₂O/CH₃CN to give the desired title compound as a white foamy solid (0.676 g, 86%): mp 178.0-182.0° C.; ¹H NMR (CDCl₃) δ0.80-0.90 (m, 12H), 1.01-1.70 (m, 30H), 1.75-2.06 (m, 12H), 2.16 (t, J=12.9 Hz, 2H), 2.79 (s, 12H), 3.03 (ABq, 4H), 3.33 (s, 12H), 3.49 (br s, 6H), 3.70 (br s, 4H), 3.96 (t, J=5.4 Hz, 4H), 4.08 (s, 2H), 5.42 (s, 2H), 5.986 (s, 1H), 5.993 (s, 1H), 6.49 (d, J=9.0 Hz, 1H), 6.50 (d, J=9.0 Hz, 1H), 6.87 (d, J=8.4 Hz, 4H), 7.38 (d, J=8.1 Hz, 4H), 7.84 (d, J=8.7 Hz, 2 H). HRMS. Calc'd for C₃₆H₅₈N₂O₄S: 614.4118. Found: 614.4148.

Example 1420

(4R-cis)-3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-[4-[[5-(1H-tetrazol-5-yl)pentyl]oxy]phenyl]-1-benzothiepin-4-ol 1,1-dioxide

Step 1: Preparation of Pentyl Bromide Intermediate

To a stirred suspension of 1.01 g (25.4 mmol, 60% oil dispersion) of sodium hydride in 150 mL of DMF was added 9.0 g (19.5 mmol) of 5-(4′-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzothiepine-1,1-dioxide (obtained from Example 1402, Step 10) in portions. After 30 minutes the reaction was cooled in a water bath (15° C.) and 4.48 g (195 mmol) of 1,5-dibromopropane was added. The reaction was stirred at ambient temperature for 1.5 hours and quenched with 50 mL of saturated NH₄Cl. The reaction was diluted with ethyl acetate, washed with water, brine, dried over MgSO₄, filtered and concentrated in vacuo. Purification by silica gel chromatography (Waters-Prep 500) using 25% ethyl acetate/hexanes afforded 10.17 g (85%) of the pentyl bromide intermediate as a colorless foam: mp 65-70° C.; ¹H NMR (CDCl₃) δ0.84-0.98 (M, 6H), 1.04-1.52 (m, 10H), 1.58-1.65 (m, 3H), 1.82 (p, J=6.8 Hz, 2H), 1.94 (p, J=7.0 Hz, 2H), 2.12-2.26 (m, 1H), 2.82 (s, 6H), 3.06 (AB_(q), J_(AB)=15.2, 45.3 Hz, 2H), 3.44 (t, J=6.7 Hz, 2H), 3.99 (t, J=6.3 Hz, 2H), 4.10 (s, 1H), 5.47 (s, 1H), 6.15 (d, J=2.7 Hz, 1H), 6.68 (dd, J=2.5, 8.4 Hz, 1H), 6.91 (d, J=8.4 Hz, 2H), 7.39 (d, J=8.4 Hz, 2H), 7.93 (d, J=8.7 Hz, 1H).

Step 2: Preparation of Pentyl Nitrile Intermediate

To a stirred solution of 378 mg (0.621 mmol) of the pentyl bromide intermediate (obtained from Step 1) in 1 mL of DMSO was added 37 mg (0.745 mmol) of sodium cyanide. The reaction was stirred at ambient temperature for 16 hours. The reaction was concentrated under a nitrogen stream and the residue partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over MgSO₄, filtered, and concentrated in vacuo to afford 278 mg (93% RPHPLC purity, ca. 75%) of the pentyl nitrile intermediate as a colorless foam: ¹H NMR (CDCl₃) δ0.86-0.96 (m, 6H), 1.02-1.21(m, 1H), 1.21-1.52 (m, 19H), 1.58-1.92 (m, 7H), 2.16-2.28 (m, 1H), 2.41 (t, J=6.9 Hz, 2H), 2.83 (s, 6H), 3.08 (AB_(q), 15.0, 47.5 Hz, 2H), 4.01 (t, J=6.2 Hz, 2H), 4.1 (s, 1H), 5.49 (s, 1H), 6.07 (d, J=2.1 Hz, 1H), 6.59 (dd, J=2.4, 8.7 Hz, 1H), 6.92 (d, J=8.1 Hz, 2H), 7.42 (d, J=8.4 Hz, 2H), 7.92 (d, J=8.7 Hz, 1H). MS (ES, M+H) m/e 555.

Step 3: Preparation of Tetrazole

A solution of 275 mg (0.5 mmol) of the nitrile intermediate (obtained from Step 2) and 666 mg (3.23 mmol) of azidotrimethyltin in 5 mL of toluene was stirred with heating at 80° C. for 60 hours. The reaction was concentrated under a nitrogen stream. Purification by reversed phase chromatography (Waters-Delta prep) using 60% water/acetonitrile afforded 226 mg of the desired title compound (75%) as a colorless foam: mp 80-85° C.; ¹H NMR (CDCl₃) δ0.83-0.95 (m, 6H), 1.30-1.52 (m, 10H), 1.52-1.73 (m, 3H), 1.79-1.99 (m, 4H), 2.14-2.26 (m, 1H), 2.91 (s, 6H), 3.02-3.22 (m, 4H), 3.92-4.06 (m, 2H), 4.16 (s, 1H), 5.47 (s, 1H), 6.28 (d, J=2.4 Hz, 1H), 6.74 (dd, J=2.7, 8.8 Hz, 1H), 6.89 (d, J=8.7 Hz, 2H), 7.37 (d, J=8.1 Hz, 2H), 7.98 (d, J=8.7 Hz, 1H). HRMS Calc'd for C₃₂H₄₈N₅O₄S: 598.3427. Found: 598.3443.

Example 1421

(4R-cis)-4-[[5-[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-1benzothiepin-5-yl]phenoxy]pentyl]oxy]-2,6-pyridinecarboxylic acid

Step 1: Preparation of Pentyl Bromide Intermediate

To a solution of 0.63 g (15.72 mmol, 60% disp) of NaH in 85 mL of DMF was add 6.0 g (13.1 mmol) of 5-(4′-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzothiepine-1,1-dioxide (obtained from Example 1402, Step 10), and the resulting solution was stirred at ambient temperature for 1 hour. To the solution was added 37.7 g (163.75 mmol) of 1,5-dibromopentane, and stirred overnight at ambient temperature. DMF was removed in vacuo and the residue was extracted with ethyl acetate and washed with brine. The extract was dried over MgSO₄, and the concentrated residue was purified by column chromatography to give the pentyl bromide intermediate: ¹H NMR (CDCl₃) δ0.90 (q, 6H), 1.05-2.0 (m, 17H), 2.2 (t, 1H), 2.8 (s, 6H), 3.0 (q, 2H), 3.4 (t, 2H), 3.95 (t, 2H), 4.1 (s, 1H), 5.42 (s, 1H), 6.0 (s, 1H), 6.5 (d, 1H), 6.9 (d, 2H), 7.4 (d, 2H), 7.9 (d, 1H).

Step 2: Esterification of Chelidamic Acid

A solution of 10 g (54.6 mmol) of chelidamic acid, 23.0 g (120.12 mmol) of 1-(3-dimethyl amino propyl)-3 ethyl carbodiimide hydrochloride, 1.33 g (10.8 mmol) of 4-dimethyl amino pyridine, and 12.4 mL (120.12 mmol) of benzyl alcohol in 100 mL of DMF was stirred at ambient temperature overnight under N₂. DMF was removed in vacuo and the residue was extracted with methylene chloride, washed with 5% NaHCO₃, 5% acetic acid, H₂O, and brine. The extract was dried over MgSO₄, and the concentrated residue was purified by column chromatography to give dibenzyl chelidamic ester: ¹H NMR (CDCl₃) δ5.4 (s, 4H), 7.4 (m, 12H).

Step 3: Preparation of Pyridinyl Benzyl Ester Intermediate

A solution of 79 mg (1.972 mmol, 60% disp) of NaH and 0.716 g (1.972 mmol) of dibenzyl chelidamic ester (obtained from Step 2) in 17.5 mL of DMF was stirred at ambient temperature for 1 hour. To the solution was added 1.0 g (1.643 mmol) of the pentyl bromide intermediate and the mixture was stirred under N₂ overnight at 40° C. DMF was removed in vacuo, and the residue was extracted with ethyl acetate and washed with brine. The extract was dried over MgSO₄, and the concentrated residue was purified by column chromatography to give the pyridinyl dibenzyl ester intermediate: ¹H NMR (CDCl₃) δ0.90 (q, 6H), 1.05-2.0 (m, 19H), 2.2 (t, 1H), 2.8 (s, 6H), 3.0 (q, 2H), 4.0 (t, 2H), 4.1 (s, 1H), 5.4 (s, 4H), 5.42 (s, 1H), 6.0 (s, 1H), 6.5 (d, 1H), 6.9 (d, 2H), 7.3-7.5 (m, 12H), 7.78 (s, 2H), 7.9 (d, 1H).

Step 4: Preparation of Pyridinyl Diacid

A suspension of 0.8813 g (0.99 mmole) of dibenzyl ester (obtained from Step 3) and 40 mg of 10% Pd/C in 35 mL of ethanol and 5 mL of THF was agitated at ambient temperature under 20 psi of hydrogen gas for 2 hours. The catalyst was filtered off, and the filtrate was concentrated to give the desired title compound as a solid: mp 143° C.; 1H NMR (THF-d8) 0.95 (q, 6H), 1.05-1.65 (m, 15H), 1.9 (m, 4H), 2.22 (t, 1H), 2.8 (s, 6H), 3.0 (t, 2H), 4.1 (s, 3H), 4.3 (s, 2H), 5.4 (s, 1H), 6.05 (s, 1H), 6.5 (d, 1H), 6.9 (d, 2H), 7.4 (d, 2H), 7.78 (d, 1H), 7.82 (s, 2H). HRMS. Calc'd for C₃₈H₅₀N₂O₉S: 711.3315. Found: 711.3322. Anal. Calc'd for C₃₈H₅₀N₂O₉S: C, 64.20; H, 7.09; N, 3.94; S, 4.51. Found: C, 62.34; H, 6.97; N, 4.01; S, 4.48.

Example 1422

(4R-cis)-[5-[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]pentyl]guanidine

Step 1: Preparation of Pentyl Azide Intermediate

To a stirred solution of 200 mg (0.328 mmol) of the pentyl bromide intermediate (obtained from Example 1420, Step 1) in 0.75 mL of DMSO was added 32 mg (0.493 mmol) of sodium azide and a catalytic amount of sodium iodide. The reaction was stirred at ambient temperature for 64 hours. The reaction was concentrated under a nitrogen stream and the residue partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over MgSO₄, filtered, and concentrated in vacuo to afford 155 mg (92% RPHPLC purity, about 76% yield) of the pentyl azide intermediate as a colorless foam. Sample was used without further purification: mp 45-50° C.; ¹H NMR (CDCl₃) δ0.83-0 93 (m, 6H), 1.03-1.48 (m, 10H), 1.54-1.74 (m, 5H), 1.78-1.86 (m, 1H), 2.14-2.26 (m, 1H), 2.81 (s, 6H), 3.06 (AB_(q), J_(AB)=15.0, 48.0 Hz, 2H), 3.31 (t, J=6.3 Hz, 2H), 3.98 (t, J=6.3 Hz, 2H), 4.09 (s, 1H), 5.47 (s, 1H), 6.10 (d, J=1.8 Hz, 1H), 6.63 (dd, J=2.7, 9.0 Hz, 1H), 6.91 (d, J=9.0 Hz, 2H), 7.39 (d, J=8.4 Hz, 2H), 7.91 (d, J=8.7 Hz, 1H). MS (FAB, M+H) m/e 571.

Step 2: Preparation of Pentyl Amine Intermediate

To a solution of 0.67 g (1.17 mmol) of the azide intermediate (obtained from Step 1) in 75 mL of ethanol was added 0.10 g of 10% palladium on carbon and the mixture shaken under 49 psi of hydrogen at ambient temperature for 3.5 hours. The reaction was filtered through celite and concentrated in vacuo to give 0.62 g (86% RPHPLC purity, ca. 84%) of pentyl amine intermediate as an off-white foam. The sample was used without further purification: mp 70-85° C.; ¹H NMR (CDCl₃) δ0.86-0.96 (m, 6H), 1.06-1.75 (m, 15H), 1.79-1.93 (m, 4H), 2.15-2.28 (m, 1H), 2.82 (s, 6H), 2.96-3.20 (m, 4H), 3.99 (t, J=6.0 Hz, 2H), 4.04-4.14 (m, 1H), 5.49 (s, 1H), 6.00 (d, J=1.5 Hz, 1H), 6.51 (d, J=9.0 Hz, 1H), 6.91 (d, J=8.4 Hz, 2H), 7.41 (d, J=8.1 Hz, 2H), 7.90 (d, J=8.7 Hz, 1H). MS (ES, M+H) m/e 545.

Step 3: Preparation of Guanidine

To a stirred solution of 258 mg (0.474 mmol) of pentyl amino intermediate (obtained from Step 2) and 81 mg (0.551 mmol) of 1H-pyrazole-1-carboxamidine hydrochloride in 1.5 mL of DMF was added 71 mg (0.551 mmol) of diisopropylethylamine. The reaction was stirred at ambient temperature for 16 hours. Purification by reversed phase chromatography (Waters-Delta prep) using 60% water/acetonitrile afforded 120 mg (43%) of the desired title compound as colorless foamy solid: mp 67.0-72.5° C.; 1H NMR (CDCl₃) δ0.89-0.93 (m, 6H), 1.05-1.17 (m, 1H), 1.26-1.90 (m, 16H), 2.07-2.24 (m, 1H), 2.81 (s, 6H), 2.99-3.19 (m, 4H), 3.98 (br s, 2H), 4.12 (s, 1H), 5.46 (s, 1H), 6.01 (d, J=2.1 Hz, 1H), 6.51 (dd, J=2.1, 8.0 Hz, 1H), 6.92 (d, J=8.1 Hz, 2H), 7.41 (d, J=7.8 Hz, 2H), 7.89 (d, J=8.7 Hz, 1H). HRMS. Calc'd for C₃₂H₅₀N₄O₄S:586.3552. Found(M+H): 587.3620.

Example 1423

(4R-cis)-N-[5-[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]pentyl]glycine

Step 1: Preparation of Pentyl Azide Intermediate

To a solution of pentyl bromide intermediate (400 mg, 0.657 mmol, obtained from Example 1420, Step 1) in dimethyl sulfoxide (20 mL) was added sodium azide (47 mg, 0.723 mmol, 1.1 eq), and the resulting clear solution was stirred at 23° C. for 16 h. The reaction solution was diluted with 100 mL ethyl acetate, then washed with water (2×100 mL) and brine (1×100 mL). The organic layer was dried (MgSO₄) and concentrated in vacuo to give 390 mg (quantitative) of pentyl azide intermediate as a yellow oil: ¹H NMR (CDCl₃) δ0.82-0.90 (m, 7H), 1.05-1.56 (m, 12H), 1.59-1.71 (m, 3H), 1.78-2.01 (m, 4H), 2.20 (t, J=8.3 Hz, 1H), 2.82 (s, 6H), 3.08 (q, 2H), 3.44 (t, J=7.7 Hz, 2H), 3.99 (t, J=7.7 Hz, 2H), 4.91 (br s, 1H), 5.47 (s, 1H), 6.13 (d, J=7.58 Hz, 1H), 6.68 (d, J=7.7 Hz, 1H), 7.14 (ABq, 4H), 7.91 (d, J=7.8 Hz, 1H).

Step 2: Preparation of Amino Ester Intermediate

A suspension of pentyl azide intermediate (390 mg, 0.684 mmol, obtained from Step 1) and 100 mg of palladium on carbon in ethanol (15 mL) was agitated under an atmosphere of hydrogen gas (48 psi) for 4.5 hours. The ethanolic suspension was filtered through celite and concentrated in vacuo to give a yellow oil. The oil was immediately diluted with acetonitrile (15 mL), followed by the addition of triethylamine (0.156 g, 1.54 mmol, 2.25 eq) and bromo acetic acid benzyl ester (0.212 g, 0.925 mmol, 1.35 eq). The reaction was stirred at 23° C. for 48 hours. The reaction was concentrated in vacuo, and the residue was dissolved in ethyl acetate (20 mL) and washed with water (2×20 mL) and brine (1×20 mL). The organic layer was dried (MgSO₄) and dried in vacuo to give 420 mg (89%) of the amino ester intermediate as a yellow oil: ¹H NMR (CDCl₃) δ0.82-0.90 (m, 6H), 1.05-1.56 (m, 14H), 1.58-1.71 (m, 3H), 1.78-2.01 (m, 4H), 2.20 (t, J=8.3 Hz, 1H), 2.75 (d, J=7.83 Hz, 1H), 2.795 (s, 6H), 3.08 (q, 2H), 3.68-3.85 (m, 2H), 3.87-4.04 (m, 2H), 4.09 (s, 1H), 5.147 (s, 1H), 5.46 (s, 1H), 5.98 (d, J=7.58, 1H), 6.50 (dd, 1H), 6.85-6.87 (m, 2.H), 7.28-7.45 (m, 5H), 7.89 (d, J=8.0 Hz, 1H). MS (ES) m/e 693.

Step 3: Preparation of Acid

A suspension of benzyl ester intermediate (0.420 g, 0.61 mmol, obtained from Step 2) and 100 mg of palladium on carbon in ethanol (15 mL) was agitated under an atmosphere of hydrogen gas (48 psi) for 16 h. The suspension was filtered through celite, and concentrated in vacuo to give 0.330 g of a yellow semi-solid. The material was triturated with diethyl ether and the remaining semi-solid was dried in vacuo to give 0.19 g (52%) of the desired title compound as a yellow semi solid: ¹H NMR (CDCl₃) δ0.86 (br s, 7H), 1.0-1.72 (m, 18H), 1.79 (br s, 2H), 1.98 (s, 2H), 2.09-2.24 (m, 2H), 2.78 (s, 6H), 2.99 (q, 2H), 3.96 (bs, 2H), 4.08 (s, 1H), 5.46 (s, 1H), 5.97 (s, 1H), 6.40-6.49 (m, 1H), 7.14 (ABq, 4H), 7.85 (t, J=7.93 Hz, 1H). MS (ES) m/e 603.

Example 1424

(4R-cis)-4-[[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]methyl]benzoic acid

Step 1: Preparation of Benzoate Intermediate

To a solution of 0.53 g (1.15 mmol) of 5-(4′-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzothiepine-1,1-dioxide (obtained from Example 1402, Step 10) in 10 mL dimethylformamide was added 35 mg (1.39 mmol) of 95% sodium hydride and stirred for 10 minutes. To the reaction mixture was added 525 mg (2.29 mmol) methyl 4-(bromomethyl)benzoate and stirred for 16 hours. Water was added to the reaction mixture, extracted with ethyl acetate, washed with brine, dried over magnesium sulfate, filtered and the solvent evaporated to afford 0.51 g (73%) of the benzoate intermediate: ¹H NMR (CDCl₃) δ0.86-0.96 (m, 6H), 1.14-1.47 (m, 10H), 1.60-1.64 (m, 1H), 2.20-2.23 (m, 1H), 2.80 (s, 6H), 2.99 (d, J=15.1 Hz, 1H), 3.15 (t, J=15.1 Hz, 1H), 3.92 (s, 3H), 4.09-4.15 (m, 1H), 5.17 (s, 2H), 5.49 (s, 1H), 5.94 (d, J=2.2 Hz, 1H), 6.50 (dd, J=8.9, 2.6 Hz, 1H), 7.00 (d, J=8.7 Hz, 2H), 7.43 (d, J=8.5 Hz, 2H), 7.53 (d, J=8.5 Hz, 2H), 7.93 (d, J=8.9 Hz, 1H), 8.06 (d, J=8.5 Hz, 2H).

Step 2: Preparation of Acid

A solution of 0.51 g (0.84 mmol) of the benzoate intermediate (obtained from Step 1) and 325 mg (2.53 mmol) of KOSi(CH₃) ₃ (Aldrich) in 16 mL THF was stirred for 3.5 hours. The THF was evaporated, water added, extracted with ethyl acetate, dried over magnesium sulfate, filtered and the solvent evaporated to afford 0.30 g (60%) of the desired title compound as a white solid: mp 156-159° C.; ¹H NMR (CDCl₃) δ0.89-0.94 (m, 6H), 1.24-1.43 (m, 10H), 1.62-1.66 (m, 1H), 2.20-2.24 (m, 1H), 2.84 (s, 6H), 3.02 (d, J=15.1 Hz, 1H), 3.17 (d, J=15.1 Hz, 1H), 4.14 (s, 1H), 5.20 (s, 2H), 5.50 (s, 1H), 6.16 (s, 1H), 6.71 (d, J=9.1 Hz, 2H), 7.03 (d, J=8.3 Hz, 2H), 7.44 (d, J=8.1 Hz, 2H), 7.57 (d, J=8.3 Hz, 2H), 7.95 (d, J=8.9 Hz, 1H), 8.13 (d, J=8.1 Hz, 2H). HRMS. Calc'd for C₃₄H₄₄NO₆S: 594.2889. Found: 594.2913.

Example 1425

(4R-cis)-1-[[4-[[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]methyl]phenyl]methyl]-pyridinium chloride

Step 1: Preparation of Chlorobenzyl Intermediate

A solution of 5-(4′-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzothiepine-1,1-dioxide (5.0 g, 10.9 mmol, obtained from Example 1402, Step 10) in acetone (100 mL) at 25° C. under N₂ was treated with powdered K₂CO₃ (2.3 g, 16.3 mmol, 1.5 eq.) and α,α′-dichloro-p-xylene (6.7 g, 38.1 mmol, 3.5 eq.) and the resulting solution was stirred at 65° C. for 48 hours. The reaction mixture was cooled to 25° C. and concentrated to ⅕ of original volume. The residue was dissolved in EtOAc (150 mL) and washed with water (2×150 mL). The aqueous layer was extracted with EtOAc (2×150 mL) and the combined organic extracts were washed with saturated aqueous NaCl (2×150 mL. The combined extracts were dried (MgSO₄) and concentrated in vacuo to provide a yellow oil. Purification by flash chromatography (5.4×45 cm silica, 25-40% EtOAc/hexane) afforded the chlorobenzyl intermediate (4.7 g, 72%) as a white foam: ¹H NMR (CDCl₃) δ0.89-0.94 (m, 6H), 1.12-1.48 (br m, 10H), 1.63 (m, 1H), 2.22 (m, 1H), 2.81 (s, 6H), 3.05 (ABq, J=15.1 Hz, J=50.0 Hz, 2H), 4.11 (d, J=8.1 Hz, 1H), 4.60 (s, 2H), 5.11 (s, 2H), 5.48 (s, 1H), 5.96 (d, J=2.4 Hz, 1H), 6.48 (dd, J=8.9, 2.6 Hz, 1H), 7.00 (d, J=8.9 Hz, 2H), 7.36-7.47 (m, 5H), 7.85 (d, J=8.9 Hz, 1H).

Step 2: Preparation of Quaternary Salt

A solution of the chlorobenzyl intermediate (1.0 g, 1.7 mmol, obtained from Step 1) in acetonitrile (5 mL) at 25° C. under N₂ was treated with pyridine (5 mL) and stirred at 35° C. for 36 hours. The pale amber solution was cooled to 25° C. and concentrated in vacuo to give the desired title compound (1.08 g, 96%) as a yellow solid: mp 154-156° C.; ¹H NMR (CDCl₃) δ0.83 (m, 6H), 1.06-1.44 (br m, 10H), 1.60 (m, 1H), 2.13 (m, 1H), 2.71 (s, 6H), 3.02 (ABq, J=15.1 Hz, J=28.4 Hz, 2H), 4.09 (s, 1H), 5.00 (s, 2H), 5.38 (s, 1H), 5.91 (d, J=2.4 Hz, 1H), 6.26 (s, 2H), 6.41 (dd, J=8.9, 2.4 Hz, 1H), 6.91 (d, J=8.7 Hz, 2H), 7.26 (m, 1H), 7.40 (d, J=7.7 Hz, 4H), 7.73 (d, J=7.9 Hz, 2H), 7.78 (d, J=8.9 Hz, 2H), 7.93 (t, J=6.8 Hz, 1H), 8.34 (t, J=7.7 Hz, 1H), 8.58 (br s, 1H), 9.69 (d, J=5.8 Hz, 2H); HRMS. Calc'd for C₃₉H₄₉N₂O₄S: 641.3413. Found: 641.3425.

Example 1426

(4R-cis)-1-[[4-[[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]methyl]phenyl]methyl]-4-aza-1-azoniabicyclo [2.2.2]octane chloride

Under N₂, a solution of 8.7 g (14.5 mmol) of the chlorobenzyl intermediate (obtained from a procedure similar to the one outlined in Example 1425, Step 1) in 60 mL of acetonitrile was added dropwise over a 30 min period to a solution of 2.9 g (26.2 mmol) of diazabicyclo[2.2.2]octane (DABCO) in 40 mL of acetonitrile at 35° C.; during the addition, a colorless precipitate was formed. The slurry was stirred at 35° C. for an additional 2 h. The product was collected and washed with 1 L of acetonitrile to give 9.6 g (93%) the title compound as a colorless crystalline solid: mp 223-230° C. (decomposed); ¹H NMR (CDCl₃) δ0.89 (m, 6H), 1.27-1.52 (br m, 10H), 1.63 (m, 1H), 2.20 (m, 1H), 2.81 (s, 6H), 3.06 (ABq, J=15.1 Hz, J=43.3 Hz, 2H), 3.16 (s, 6H), 3.76 (s, 6H), 4.11 (d, J=7.7 Hz, 1H), 5.09 (s, 2H), 5.14 (s, 2H), 5.48 (s, 1H), 5.96 (s, 1H), 6.49 (d, J=8.9 Hz, 1H), 6.99 (d, J=8.0 Hz, 2H), 7.26 (m, 1H), 7.44 (d, J=8.0 Hz, 2H), 7.52 (d, J=7.4 Hz, 2H), 7.68 (d, J=7.4 Hz, 2H), 7.87 (d, J=8.9 Hz, 1H); HRMS. Calc'd for C₄₀H₅₆N₃O₄S: 674.3992. Found: 674.4005.

Example 1426a

(4R-cis)-1-[[4-[[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]methyl]phenyl]methyl]-4-aza-1-azoniabicyclo[2.2.2]octane chloride

A solution of the chlorobenzyl intermediate (4.6 g, 7.7 mmol, obtained from Example 1425, Step 1) in acetonitrile (100 mL) at 25° C. under N₂ was treated with diazabicyclo[2.2.2]-octane (DABCO, 0.95 g, 8.5 mmol, 1.1 eq.) and stirred at 35° C. for 2 hours, during which time a white solid precipitated out. The white solid was collected, washed with CH₃CN and recrystallized from CH₃OH/Et₂O to give the title compound (4.95 g, 91%) as a white solid: mp 223-230° C. (decomposed); ¹H NMR (CDCl₃) δ0.89 (m, 6H), 1.27-1.52 (br m, 10H), 1.63 (m, 1H), 2.20 (m, 1H), 2.81 (s, 6H), 3.06 (ABq, J=15.1 Hz, J=43.3 Hz, 2H), 3.16 (s, 6H), 3.76 (s, 6H), 4.11 (d, J=7.7 Hz, 1H), 5.09 (s, 2H), 5.14 (s, 2H), 5.48 (s, 1H), 5.96 (s, 1H), 6.49 (d, J=8.9 Hz, 1H), 6.99 (d, J=8.0 Hz, 2H), 7.26 (m, 1H), 7.44 (d, J=8.0 Hz, 2H), 7.52 (d, J=7.4 Hz, 2H), 7.68 (d, J=7.4 Hz, 2H), 7.87 (d, J=8.9 Hz, 1H); HRMS. Calc'd for C₄₀H₅₆N₃O₄S: 674.3992. Found: 674.4005.

Example 1427

4R-cis)-N-(Carboxymethyl)-N-[[4-[[4-[3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]methyl]phenyl]methyl]glycine

Step 1: Preparation of Chlorobenzyl Intermediate

To a stirred solution of 144 mg (3.59 mmol, 60% disp) of NaH in 29 mL of DMF was added 1.5 g (3.26 mmol) of 5-(4′-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzothiepine-1,1-dioxide (obtained from Example 1402, Step 10), and the resulting solution was stirred at ambient temperature for 45 min. To the solution was added 7.13 g (40.75 mmol) of dichloro p-xylene, and the mixture was stirred overnight. DMF was removed in vacuo, and the residue was extracted with ethyl acetate and washed with brine. The extract was dried over MgSO₄, and the concentrated residue was purified by column chromatography to give the chlorobenzyl intermediate: ¹H NMR (CDCl₃) δ0.90 (q, 6H), 1.05-1.65 (m, 11H), 2.2 (t, 1H), 2.8 (s, 6H), 3.0 (q, 2H), 4.1 (d, 1H), 4.6 (s, 2H), 5.1 (s,2H), 5.5 (s, 1H), 6.0 (s, 1H), 6.6 (d, 1H), 7.0 (d, 2H), 7.4 (m, 6H), 7.8 (d, 1H).

Step 2: Preparation of Amino Diester

A mixture of 1.03 g (1.72 mmol) of chlorobenzyl intermediate (obtained from Step 1), 1.63 g (8.6 mmol) of diethyl amino diacetate, and 0.72 g (8.6 mmol) of NaHCO₃ in 30 mL of DMF was stirred at 100° C. for 6 hours. DMF was removed in vacuo and the residue was extracted with ether and washed with brine. The extract was dried over MgSO₄, and the concentrated residue was purified by column chromatography to give amino diester intermediate: ¹H NMR (CDCl₃) δ0.90 (q, 6H), 1.05-1.65 (m, 17H), 2.2 (t, 1H), 2.8 (s, 6H), 3.0 (q, 2H), 3.55 (s, 4H), 3.95 (s, 2H), 4.1-4.2 (m, 5H), 5.05 (s, 2H), 5.42 (s, 1H), 5.95 (s, 1H), 6.5 (d, 1H), 7.0 (d, 2H), 7.4 (s, 6H), 7.8 (d, 1H).

Step 3: Preparation of Amino Diacid

A solution of 0.863 g (1.15 mmol) of dibenzyl ester (obtained from Step 2) and 0.232 g (5.52 mmol) of LiOH in 30 mL of THF and 30 mL of water was stirred at 40° C. under N₂ for 4 hours. The reaction mixture was diluted with ether and washed with 1% HCl. The aqueous layer was extracted twice with ether, and the combined extracts were washed with brine, dried over MgSO₄, and concentrated in vacuo to give the desired title compound as a solid: mp 175° C.; ¹H NMR (THF-d8) 0.95 (q, 6H), 1.05-1.65 (m, 11H), 2.22 (t, 1H), 2.8 (s, 6H), 3.0 (t, 2H), 3.5 (s, 4H), 3.9 (s, 2H), 4.1 (d, 1H), 5.1 (s, 2H), 5.4 (s, 1H), 6.05 (s, 1H), 6.5 (d, 1H), 7.0 (d, 2H), 7.4 (m, 6H), 7.78 (d, 1H). HRMS. Calc'd for C₃₈H₅₀N₂O₈S: 695.3366. Found: 695.3359. Anal. Calc'd for C₃₈H₅₀N₂O₈S: C, 65.68; H, 7.25; N, 4.03; S, 4.61. Found: C, 64.95; H, 7.32; N, 3.94; S, 4.62.

Example 1428

(4R-cis)-4-[[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]methyl]-1-methylpyridinium salt with trifluoroacetic acid (1:1)

Step 1: Preparation of Picolyl Intermediate

To a stirred solution of 12.0 g (26.1 mmol) of 5-(4′-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzothiepine-1,1-dioxide (obtained from Example 1402, Step 10) in 200 mL of DMF was added 1.4 g (60% oil dispersion, 35 mmol) of sodium hydride and the reaction stirred at ambient temperature for one hour. 5.99 g (36.5 mmol) of 4-picolyl chloride hydrochloride was treated with cold saturated NaHCO₃ solution and extracted with diethyl ether. The ethereal extracts were washed with brine, dried over MgSO₄, and filtered. The reaction was cooled in an ice bath and the solution of 4-picolyl chloride in diethyl ether was added. The reaction was stirred at ambient temperature for 17 hours. The reaction was quenched with 25 mL of saturated NH₄Cl, diluted with 600 mL ethyl acetate washed with 4×250 mL water, brine, dried over MgSO₄, filtered and concentrated in vacuo. Purification by silica gel chromatography (Waters-prep 500) using 60% ethyl acetate/hexanes afforded 11.05 g (77%) of the picolinyl intermediate as a colorless solid: mp 95-98° C.; ¹H NMR (CDCl₃) δ0.86-0.96 (m, 6H), 1.02-1.52 (m, 10H), 1.58-1.70 (m, 1H), 2.16-2.29 (m, 1H), 2.81 (s, 6H), 3.07 (AB_(q), J_(AB)=15.3, 49.6 Hz, 2H), 4.10 (d, J=7.5 Hz, 1H), 5.15 (s, 2H), 5.50 (s, 1H), 5.94 (d, J=2.7 Hz, 1H), 6.51 (dd, J=2.4, 8.7 Hz, 1H), 7.00 (d, J=9.0 Hz, 2H), 7.39 (d, 6.0 Hz, 2H), 7.44 (s, J=8.7 Hz, 2H), 7.89 (d, J=9.0 Hz, 2H), 8.63 (dd, J=1.6, 4.8 Hz, 2H).

Step 2: Preparation of Quaternary Salt

To a stirred solution of 0.41 g (0.74 mmol) of picolinyl intermediate (obtained from Step 1) in 10 mL of acetonitrile and 3 mL of dichloromethane was added 137 mg (0.97 mmol) of iodomethane. The reaction was stirred at ambient temperature for 16 hours, then concentrated under a nitrogen stream. Purification by reversed phase chromatography (Waters-Delta prep) using 60-55% water/acetonitrile afforded 0.304 g (60%) of the desired title compound as a colorless solid: mp 96-99° C.; ¹H NMR (CDCl₃) δ0.85-0.95 (m, 6H), 1.03-1.52 (m, 10H), 1.57-1.70 (m, 1H), 2.12-2.27 (m, 1H), 2.84 (s, 6H), 3.09 (AB_(q), J_(AB)=15.0, 27.9 Hz, 2H), 4.11 (s, 1H), 4.46 (s, 3H), 5.37 (s, 2H), 5.50 (s, 1H), 6.07 (d, J=2.4 Hz, 1H), 6.61 (dd, J=2.5, 8.7 Hz, 1H), 7.02 (d, J=8.7 Hz, 2H), 7.48 (d, J=7.2 Hz, 2H), 7.90 (d, J=8.7 Hz, 1H), 8.14 (d, J=6.3 Hz, 2H), 8.80 (d, J=6.6 Hz, 2H). HRMS Calc'd for C₃₃H₄₅N₂O₄S: 565.3100. Found: 565.3125.

Example 1429

(4R-cis)-4-[[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]methyl]-1-methylpyridinium, methanesulfonate (salt)

To a stirred solution of 6.5 g (11.8 mmol) of picolyl intermediate (obtained from Example 1428, Step 1) in 140 mL of acetonitrile heated at 70° C. was added 1.56 g (14.6 mmol) methanesulfonic acid methyl ester. Heating was continued at 70° C. for 15 hours. The reaction was cooled and diluted with 50 mL of ethyl acetate. The solid was collected by vacuum filtration to give 6.14 g (79%). The filtrate was concentrated in vacuo and the residue crystallized from hot acetonitrile to give 1.09 g (14%). A total of 7.23 g (93%) of the desired title compound was obtained as an off-white solid: mp 232-233.5° C.; ¹H NMR (CDCl₃) δ0.66-0.76 (m, 6H), 0.85-0.95 (m, 1H), 0.95-1.35 (m, 9H), 1.42-1.54 (m, 1H), 1.95-2.22 (m, 1H), 2.50 (s, 1H), 2.56 (s, 3H), 2.63 (s, 6H), 2.91 (AB_(q), J=16.5, 24.0 Hz, 2H), 3.88 (s, 1H), 4.40 (s, 3H), 5.21 (s, 3H), 5.78 (d, J=2.4 Hz, 1H), 6.31 (dd, J=2.5, 8.7 Hz, 1H), 6.84 (d, J=8.7 Hz, 2H), 7.31 (d, J=8.4 Hz, 2H), 7.64 (d, J=8.7 Hz, 1H), 8.0 (d, J=6.6 Hz, 2H), 9.02 (d, J=6.6 Hz, 2H). HRMS Calc'd for C₃₃H₄₅N₂O₄S: 565.3100. Found: 656.3087. Anal. Calc'd for C₃₄H₄₈N₂O₇S₂: C, 61.79; H, 7.32; N, 4.24; S, 9.70. Found: C, 61.38, H, 7.47; N, 4.22; S, 9.95.

Example 1430

(4R-cis)-6-[[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]methyl]-2-pyridinepropanoic acid

Step 1: Preparation of Picolinyl Chloride Intermediate

To a solution of 5-(4′-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzothiepine-1,1-dioxide (1 g, 2.1 mmol, obtained from Example 1402, Step 10) in acetone (50 mL) was added anhydrous K₂CO₃ (0.45 g, 3.2 mmol), tetrabutylammonium iodide (0.1 g, 0.2 mmol) and 2,6-bischloromethylpyridine (1.2 g, 10.8 mmol). The flask was equipped with nitrogen gas adapter and magnetic stirrer. The reaction was heated to reflux for overnight. After 18 hours, the reaction was diluted with ether and washed with water and brine (30 mL). The organic layers were dried over MgSO₄, filtered and concentrated in vacuo. Chromatographic purification through silica gel, eluting with 25% EtOAc/Hexane gave 0.75 g (55%) of the picolyl chloride intermediate as an oil (0.70 g, 55%): ¹H NMR (CDCl₃) δ0.84-0.95 (m, 6H), 1.02-1.5 (m, 10H), 1.56-1.66 (m, 1H), 2.14-2.24 (m, 1H), 2.80 (s, 6H) 3.05 (ABq, 2H), 4.10 (d, 2H), 4.65 (s, 2H), 5.20 (s, 2H), 5.45 (s, 1H), 5.95 (s, 1H), 6.50 (d, 1H), 7.0 (d, 2H),7.35-7.50 (m, 4H), 7.70-7.85 (m, 2H).

Step 2: Preparation of Pyridinyl Malonate Intermediate

Dibenzyl malonate (1.42 g, 5.01 mmol) in DMF (20.0 mL) and sodium hydride (0.13 g, 3.3 mmol) were placed in a dry three-neck flask. The flask was equipped with nitrogen gas adapter and magnetic stirrer. The picolyl chloride intermediate (1 g, 1.67 mmol) was added and heated at 90° C. for overnight. The reaction was cooled and extracted with 5% HCl with methylene chloride and washed with water (25 mL), and brine (50 mL). The organic layers were dried over MgSO_(4,) filtered and concentrated. The residue was purified by C-18 reversed phase column eluting with 50% acetonitrile/water and gave pyridinyl malonate intermediate as a white foamy solid (1 g, 71%): ¹H NMR (CDCl₃) δ0.84-0.95 (m, 6H), 1.02-1.5 (m, 10H), 1.56-1.66 (m, 1H), 2.14-2.24 (m, 1H), 2.80 (s, 6H) 3.05 (ABq, 2H), 3.22 (d, 2H), 4.05 (d, 1H), 4.16 (t, 1H), 5.02(s, 2H), 5.08 (s, 4H), 5.44 (s, 1H), 5.97 (s, 1H), 6.96-7.10 (m, 3H), 7.20-7.32 (m, 12H), 7.5 (t, 1H), 7.9 (d, 1H).

Step 3: Preparation of Pyridinyl Acid

The pyridinyl malonate intermediate (0.6 g, 0.7 mmol, obtained from Step 2), THF/water (25.0 mL, 1:1) and lithium hydroxide monohydrate (0.14 g, 3.4 mmol) were placed in a 100 mL round-bottom flask. The reaction was stirred at ambient temperature overnight. After 18 hours, the reaction was extracted with 1% HCl and ether and then washed with water (20 mL) and brine (30 mL). The organic layers were dried over MgSO₄, filtered and concentrated in vacuo gave the desired title compound as a white solid (0.44 g, 90%): mp 105-107° C.; ¹H NMR (CDCl₃) δ0.84-0.95 (m, 6H), 1.02-1.5 (m, 10H), 1.56-1.66 (m, 1H), 2.14-2.24 (m, 1H), 2.80 (s, 6H),3.05 (m, 2H), 3.10 (ABq, 2H), 3.22 (m, 2H), 4.05 (s, 1H), 5.30 (s, 2H), 5.50 (s, 1H), 5.97 (s, 1H), 6.50 (d, 1H), 7.02 (d, 2H), 7.3 (d, 1H), 7.42 (d, 2H), 7.58 (d, 1H), 7.8-7.9 (m, 2H). HRMS. Calc'd for C₃₅H₄₆N₂O₆S: 623.3155. Found: 623.3188.

Example 1431

(4R-cis)-N-(Carboxymethyl)-N-[[6-[[4-[3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]methyl]-2-pyridinyl]methyl]glycine

Step 1: Preparation of Pyridinyl Diester Intermediate

A mixture of diethyl aminodiacetate (8 g, 68 mmol) and sodium carbonate (0.63 g, 5.9 mmol) was treated with picolyl chloride intermediate (0.72 g, 1.2 mmol, obtained from Example 1430, Step 1), and stirred at 160° C. for three hours. The reaction was cooled and diluted with ether and washed with 1% HCl, water (25 mL), and brine (50 mL). The combined extracts were dried over MgSO₄, filtered and concentrated in vacuo. The residue was purified by distillation in the Kugelrohr to give pyridinyl diester intermediate as a yellowish foamy solid (0.72 g, 80%): ¹H NMR (CDCl₃) δ0.84-0.95 (m, 6H), 1.02-1.5 (m, 16H), 1.56-1.66 (m, 1H), 2.14-2.24 (m, 1H), 2.80 (s, 6H) 3.05 (ABq, 2H), 3.70 (s, 4H), 4.2-4.4 (m, 6H), 5.30 (s, 2H), 5.56 (s, 1H),6.02 (s, 1H), 6.60 (d, 1H), 7.10 (d, 2H),7.50 (m, 3H), 7.61 (d, 1H), 7.80 (t, 1H), 7.95 (d, 1H). HRMS. Calc'd for C₄₁H₅₇N₃O₈S: 752.3945. Found: 752.3948.

Step 2: Preparation of Pyridinyl Diacid

A mixture of pyridine-aminodiacetate intermediate (0.7 g, 0.93 mmol, obtained from Step 1), and lithium hydroxide monohydrate (0.18 g, 4.5 mmol) in THF/water (25.0 mL, 1:1) was stirred at 40° C. overnight (18 hours). The reaction mixture was diluted with ether and washed with 1% HCl, water (20 mL), and brine (30 mL). The organic layers were dried over MgSO₄, filtered and concentrated in vacuo to give the desired title compound as a white solid (0.44 g, 90%): mp 153-155° C.; ¹H NMR (CDCl₃) δ0.84-0.95 (m, 6H), 1.02-1.5 (m, 10H), 1.56-1.66 (m, 1H), 2.14-2.24 (m, 1H), 2.80 (s, 6H), 3.10 (ABq, 2H), 3.90 (m, 3H), 4.05 (s, 1H), 4.40 (s, 2H), 5.20 (s, 2H), 5.50 (s, 1H), 5.97 (s, 1H), 6.50 (d, 1H), 7.02 (d, 2H), 7.3 (d, 1H), 7.42 (d, 2H), 7.58 (d, 1H), 7.8-7.9 (m, 2H). HRMS. Calc'd for C₃₇H₄₉N₃O₈S: 696.3319. Found:696.3331.

Example 1432

(4S-cis)-[2-[2-[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]ethoxy]ethyl]propanedioic acid

Step 1: Preparation of Bromoethyl Ether Intermediate

To a stirred solution of 0.192 g (4.785 mmol, 60% disp) of NaH in 28 mL of DMF was added 2.0 g (4.35 mmol) of 5-(4′-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzothiepine-1,1-dioxide (obtained from Example 1402, Step 10), and the resulting solution was stirred at ambient temperature for 30 min. To the solution was added 13.2 g (54.38 mmol) of bis(2-bromoethyl)ether, and stirring was continued at ambient temperature under N₂ overnight. DMF was removed in vacuo and the residue was extracted with ethyl acetate and washed with brine. The extract was dried over MgSO₄, and the concentrated residue was purified by column chromatography to give bromoethyl ether intermediate: ¹H NMR (CDCl₃) δ0.90 (q, 6h), 1.05-1.65 (m, 11H), 2.2 (t, 1H), 2.8 (s, 6H), 3.0 (q, 2H), 3.5 (t, 2H), 3.9 (m, 4H), 4.1 (d, 1H), 4.2 (d, 2H), 5.42 (s, 1H), 5.95 (s, 1H), 6.5 (d, 1H), 6.95 (d, 2H), 7.4 (d, 2H), 7.9 (d, 1H).

Step 2: Preparation of Diester Intermediate

To a mixture of 94 mg (2.34 mmol, 60% disp) of NaH in 45 mL of THF and 15 mL of DMF at 0° C. was added 1.33 g (4.68 mmol) of dibenzyl malonate (Aldrich), and the resulting solution was stirred at ambient temperature for 15 min, followed by the addition of 0.95 g (1.56 mmol) of bromoethyl ether intermediate (obtained from Step 1). The mixture was stirred under N₂ at 80° C. overnight. Solvent was removed in vacuo and the residue was extracted with methylene chloride and washed with brine. The extract was dried over MgSO₄, and the concentrated residue was purified by column chromatography to give the diester intermediate: ¹H NMR (CDCl₃) δ0.90 (q, 6H), 1.05-1.65 (m, 11H), 2.2-2.3 (m, 3H), 2.8 (s, 6H), 3.0 (q, 2H), 3.6 (t, 2H), 3.7 (m, 3H), 4.1 (m, 3H), 5.1 (s, 4H), 5.42 (s, 1H), 5.9 (s, 1H), 6.5 (d, 1H), 6.9 (d, 2H), 7.3 (m, 10H), 7.4 (d, 2H), 7.9 (d, 1H).

Step 3: Preparation of Diacid

A suspension of 0.761 g (0.935 mmol) of the diester intermediate (obtained from Step 2) and 35 mg of 10% Pd/C in 25 mL of ethanol and 5 mL of THF was agitated at ambient temperature under 20 psi of hydrogen gas for 2 hours. The catalyst was filtered off, and the filtrate was concentrated to give the desired title compound as a solid: mp 119.5° C.; ¹H NMR (THF-d8) 0.95 (q, 6H), 1.05-1.65 (m, 11H), 2.1 (q, 2H), 2.25 (t, 1H), 2.8 (s, 6H), 3.0 (t, 2H), 3.47 (q, 2H), 3.58 (s, 1H), 3.78 (t, 2H), 4.08 (d, 1H), 4.15 (t, 2H) , 5.4 (s, 1H), 6.05 (s, 1H), 6.55 (d, 1H), 6.98 (d, 2H), 7.42 (d, 2H), 7.8 (d, 1H). HRMS. Calc'd for C₃₃H₄₇NO₉S: 632.2893. Found: 632.2882. Anal. Calc'd for C₃₃H₄₇NO₉S: C, 62.54; H, 7.47; N, 2.21; S, 5.06. Found: C, 61.75; H, 7.56; N, 2.13; S, 4.92.

Example 1433

(4R-cis)-a-[[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]methyl]-w-methoxypoly(oxy-1,2-ethanediyl)

Step 1: Preparation of Monomethyl PEG Mesylate Intermediate

To a solution of 20 g of monomethyl ether PEG in 100 mL of methylene chloride was added 2.2 g (22 mmol) of triethyl amine, and to the resulting solution at 0° C. was added dropwise 2.5 g (22 mmol) of methanesulfonyl chloride. The resulting solution was stirred overnight at ambient temperature, and the triethyl amine hydrochloride was filtered off to give the monomethyl PEG mesylate intermediate which was used in the next Step without further purification and characterization.

Step 2: Preparation of Polyethylene-linked Benzothiepene

A mixture of 38 mg (1.52 mmol 95%) of NaH and 0.7 g (1.52 mmol) of 5-(4′-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzothiepine-1,1-dioxide (obtained from Example 1402, Step 10) in 5.5 mL of DMF was stirred at ambient temperature under N₂ for 30 min. To the solution was added 0.55 g (0.51 mmol) of the mesylate PEG intermediate (obtained from Step 1) in 5.5 mL of DMF, and the resulting solution was stirred overnight under N₂ at 50° C. DMF was removed in vacuo and the residue was extracted with methylene chloride and washed with brine. The extract was dried over MgSO₄, and the concentrated residue was purified by column chromatography to give the desired title compound as an oil: ¹H NMR (CDCl₃) δ0.9 (q, 6h), 1.05-1.65 (m, 11H), 2.2 (t, 1H), 2.8 (s, 6H), 3.0 (q, 2H), 3.4 (s, 4H), 3.5-3.85 (m, 95H), 4.1 (s, 1H), 4.15 (t, 2H), 5.5 (s, 1H), 6.05 (s, 1H), 6.6 (d, 1H), 6.9 (d, 2H), 7.4 (d, 2H), 7.9 (d, 1H).

Example 1434

Preparation of

The 3-aminobenzothiepene prepared in Step 5 of Example 1398 (0.380 g, 0.828 mmol), sodium hydroxide (0.35 mL, 0.875 mmol, 10% in H₂O) and toluene (0.50 mL) were combined in a 10 mL round-bottom flask. The reaction flask was purged with N₂, equipped with magnetic stirrer, and cooled to 0° C. A solution of 3-chloropropyl chloroformate (1.440 g, 1.10 mmol, 12% in CH₂Cl₂/THF) was added. After 3.5 hrs, toluene (3.0 mL) was added, and the mixture was washed with H₂O (2×4 mL), dried (MgSO₄), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel eluting with 20% EtOAc/hexane and concentrated in vacuo gave a white solid (0.269 g, 56%). ¹H NMR (CDCl₃) δ0.87-0.93 (m, 6H), 1.05-1.70 (m, 11H), 2.14 (t, J=6.3 Hz, 2H), 2.15-2.25 (m, 1H), 2.81 (s, 6H), 3.07 (ABq, 2H), 3.64 (t, J=6.3 Hz, 2H), 4.11 (d, J=7.5 Hz, 1H), 4.33 (t, J=6.0 Hz, 2H), 5.50 (s, 1H), 5.99 (d, J=2.4 Hz, 1H), 6.51 (dd, J=9.0, 2.7 Hz, 1H), 6.65 (s, 1H), 7.23 (d, J=7.8 Hz, 1H), 7.34-7.39 (m, 2H), 7.54 (d, J=7.2 Hz, 1H), 7.89 (d, 8.7 Hz, 1H). HRMS (M+H). Calc'd for C₃₀H₄₄N₂O₅SCl: 579.2659. Found: 579.2691.

Example 1435

Preparation of

1,4-Diazabicyclo(2.2.2)octane (0.0785 g, 0.700 mmol) and acetonitrile (1.0 mL) were combined in a 10 mL round-bottom flask. The reaction flask was purged with N₂, equipped with magnetic stirrer, and heated to 37° C. A solution of the product of Example 1434 (0.250 g, 0.432 mmol) in acetonitrile (2.50 mL) was added. After 2.5 hrs, 1,4-diazabicyclo(2.2.2)octane (0.0200 g, 0.178 mmol) was added. After 64 hrs, 1,4-diazabicyclo(2.2.2)octane (0.0490 g, 0.437 mmol) was added. After 24 hrs, the reaction mixture was cooled to R.T. and concentrated in vacuo. The crude product was dissolved in acetonitrile (2.0 mL) and precipitated with ethyl ether (10.0 mL). The precipitate was filtered to yield a white solid. This trituration method was repeated, followed by concentrated in vacuo to give a white solid (0.185 g, 62%). mp 218.0-225.0° C.; ¹H NMR (CD₃OD) δ0.90 (m, 6H), 1.05-1.55 (m, 10H), 1.16 (t, J=6.6 Hz, 2H), 1.78 (m, 1H), 2.12 (m, 3H), 2.76 (s, 6H), 3.10 (m, 2H), 3.17 (t, J=7.2 Hz, 6H), 3.30-3.50 (m, 8H), 4.10 (s, 1H), 4.21 (t, J=5.4 Hz, 2H), 5.31 (s, 1H), 6.10 (s, 1H), 6.55 (d, J=7.2 Hz, 1H), 7.25 (d, J=6.9 Hz, 1H), 7.33-7.42 (m, 2H), 7.56 (s, 1H), 7.76 (d, J=9.0 Hz, 1H). HRMS. Calc'd for C₃₆H₅₅N₄O₅SCl: 655.3893. Found: 655.3880.

Example 1436

3-Chloromethylbenzoate chloride (2.25 mL/15.8 mmol) and acetone (8.0 mL) were combined in a 25 mL round-bottom flask. The reaction flask was cooled to 0° C., and an aqueous solution of sodium azide (1.56 g in 5.50 mL/24.0 mmol) was added. After 1.5 hrs, the reaction mixture was poured into ice water (80.0 mL), extracted with ethyl ether (2×25 mL), dried (MgSO₄), and concentrated in vacuo to give a colorless oil (2.660 g, 86%). ¹H NMR (CDCl₃) δ4.62 (s, 2H), 7.47 (t, J=7.8 Hz, 1H), 7.66 (d, J=7.8 Hz, 1H), 7.99 (d, J=7.8 Hz, 1H), 8.05 (s, 1H).

Step 2.

3-Chloromethylbenzoyl azide (0.142 g, 0.726 mmol) and toluene (2.0 mL) were combined in a 10 mL round-bottom flask. The reaction flask was purged with N₂, equipped with magnetic stirrer, and heated to 110° C. After 2 hrs, the reaction mixture was cooled to R.T, and the 3-aminobenzothiepene prepared in Step 5 of Example 1398 (0.365 g, 0.796 mmol) was added. After 2.25 hrs, the mixture was heated to 50° C. After 0.75 hrs, 3-chloromethylbenzoyl azide (0.025 g, 0.128 mmol) was added, and the reaction mixture was heated to reflux. After 0.5 hrs, the reaction mixture was cooled to R.T. and concentrated in vacuo. Purification by flash chromatography on silica gel eluting with 20-30% EtOAc/hexane and concentrated in vacuo gave a white foamy solid (0.309 g, 62%). ¹H NMR (CDCl₃) δ0.71 (t, J=5.4 Hz, 3H), 0.88 (t, J=6.3 Hz, 3H), 1.03-1.60 (m, 11H), 1.85 (d, 6.3 Hz, 1H), 2.27 (m, 1H), 2.76 (s, 6H), 3.15 (t, 2H), 4.17 (d, J=6.6 Hz, 1H), 4.48 (s, 2H), 5.42 (s, 1H), 6.07 (s, 1H), 6.99 (d, J=7.5 Hz), 7.18-7.26 (m, 2H), 7.30-7.41 (m, 3H), 7.63 (s, 1H), 7.86 (d, J=9.0 Hz, 2H), 7.96 (s, 1H), 8.17 (s, 1H). HRMS (M+Li). Calculated for C₃₄H₄₄N₃O₄SClLi: 632.2901. Found: 632.2889.

Example 1437

Preparation of

1,4-Diazabicyclo(2.2.2)octane (0.157 g, 1.40 mmol) and acetonitrile (1.00 mL) were combined in a 10 mL round-bottom flask. The reaction flask was purged with N₂ and equipped with magnetic stirrer. A solution of the product of Example 1436 (0.262 g, 0.418 mmol) in acetonitrile (2.70 mL) was added. After 2.5 hrs, a white precipitate had had formed. Ethyl ether (6.0 mL) was added, and the precipitate was filtered, washed with ethyl ether, and dried in vacuo to yield a white solid (0.250 g, 80%). mp 246.0-248.0° C.; ¹H NMR (CD₃OD) δ0.88 (m, 6H), 1.03-1.55 (m, 10H), 1.76 (m, 1H), 2.11 (m, 1H), 2.74 (s, 6H), 3.11 (m, 8H), 3.37 (m, 6H), 4.12 (s, 1H), 4.39 (s, 2H), 5.31 (s, 1H), 6.11 (s, 1H), 6.52 (dd, J=8.7, 1.8 Hz, 1H), 7.09 (d, J=7.2 Hz, 1H), 7.23 (d, J=6.9 Hz, 1H), 7.32-7.38 (m, 2H), 7.47 (m, 2H), 7.58 (s, 1H), 7.73 (d, J=8.7 Hz, 2H). HRMS. Calculated for C₄₀H₅₆N₅O₄SCl: 702.4053. Found: 702.4064. Anal. Calculated for C₄₀H₅₆N₅O₄SCl: C, 65.06; H, 7.64; N, 9.48; S, 4.34; Cl, 4.80. Found: C, 64.90; H, 7.77; N, 9.42; S, 4.16; Cl, 4.89.

Examples 1438-1454

The compounds of Examples 1438 through 1454 can be prepared in accordance with one or more of the synthetic schemes previously disclosed in this application or using methods known to those skilled in the art.

R^(5m) 1438.

1439.

1440.

1441.

1442.

1443.

1444.

1445.

1446.

1446.

1447.

1448.

1449.

1450.

1451.

1452.

1453.

1454.

Example 1455

The 3-aminobenzothiepine of step 5 of Example 1398 (0.0165 g/0.0360 mmol), M-NCO-5000 (0.150 g/0.30 mmol) (Methoxy-PEG-NCO, MW 5000, purchased from Shearwater Polymers Inc., 2130 Memorial Parkway, SW, Huntsville, Ala. 35801), and CDCl₃ (0.7 mL) were combined in an 8 mm NMR tube. The tube was purged with N₂. After 72 hrs, the reaction mixture was heated to 50° C. After 24 hrs, an additional aliquot of the 3-aminobenzothiepine of step 5 of Example 1398 (0.0077 g/0.017 mmol) was added. After 24 hrs, the reaction mixture was transferred to a 2 mL vial and evaporated to dryness with a N₂ purge. The resulting white solid was dissolved in hot ethyl ether (2.0 mL) and ethyl acetate (0.057 mL/4 drops), cooled to precipitate and filtered. This precipitation procedure was repeated until no starting material was detected in the precipitate (TLC: SiO₂/80% EtOAc/hexanes). Concentrated in vacuo to give a white solid (0.0838 g/51%). ¹H NMR (CDCl₃) d 0.82-0.90 (m, 6H), 1.05-1.49 (m, 14H), 1.18 (t, J=6.8 Hz, 2H), 1.59 (bt, 1H), 2.18 (bt, 1H), 2.34 (s, 2H), 2.78 (s, 6H), 3.04 (ABq, 2H), 3.35-3.80 (m, 625H), 4.09 (d, J=7.2 Hz, 2H), 5.42 (s, 1H), 5.78 (s, 1H), 6.04 (d, J=1.6 Hz, 1H), 6.47 (dd, J=6.4, 3.2 Hz, 1H), 7.07 (d, J=7.6 Hz, 1H), 7.31 (bs, 1H), 7.60 (d, J=7.6 Hz, 1H), 7.66 (s, 1H), 7.85 (d, J=8.8 Hz, 1H). Mass spectroscopy data also verified desired product.

Biological Assays

The utility of the compounds of the present invention is shown by the following assays. These assays are performed in vitro and in animal models essentially using a procedure recognized to show the utility of the present invention.

In Vitro Assay of Compounds that Inhibit IBAT-mediated Uptake of [¹⁴C]-Taurocholate (TC) in H14 Cells

Baby hamster kidney cells (BHK) transfected with the cDNA of human IBAT (H14 cells) are seeded at 60,000 cells/well in 96 well Top-Count tissue culture plates for assays run within in 24 hours of seeding, 30,000 cells/well for assays run within 48 hours, and 10,000 cells/well for assays run within 72 hours.

On the day of assay, the cell monolayer is gently washed once with 100 μl assay buffer (Dulbecco's Modified Eagle's medium with 4.5 g/L glucose+0.2% (w/v) fatty acid free bovine serum albumin—(FAF)BSA). To each well 50 μl of a two-fold concentrate of test compound in assay buffer is added along with 50 μl of 6 μM [¹⁴C]-taurocholate in assay buffer (final concentration of 3 μM [¹⁴C]-taurocholate). The cell culture plates are incubated 2 hours at 37° C. prior to gently washing each well twice with 100 μl 4° C. Dulbecco's phosphate-buffered saline (PBS) containing 0.2% (w/v) (FAF)BSA. The wells are then gently washed once with 100 μl 4° C. PBS without (FAF)BSA. To each 200 μl of liquid scintillation counting fluid is added, the plates are heat sealed and shaken for 30 minutes at room temperature prior to measuring the amount of radioactivity in each well on a Packard Top-Count instrument.

In Vitro Assay of Compounds that Inhibit Uptake of [¹⁴C]-Alanine

The alanine uptake assay is performed in an identical fashion to the taurocholate assay, with the exception that labeled alanine is substituted for the labeled taurocholate.

In Vivo Assay of Compounds that Inhibit Rat Ileal Uptake of [¹⁴C]-Taurocholate into Bile

(See “Metabolism of 3α,7β-dihydroxy-7α-methyl-5β-cholanoic acid and 3α,7β-dihydroxy-7α-methyl-5β-cholanoic acid in hamsters” in Biochimica et Biophysica Acta 833 (1985) 196-202 by Une et al.)

Male wistar rats (200-300 g) are anesthetized with inactin @100 mg/kg. Bile ducts are cannulated with a 10″ length of PE10 tubing. The small intestine is exposed and laid out on a gauze pad. A canulae (⅛″ luer lock, tapered female adapter) is inserted at 12 cm from the junction of the small intestine and the cecum. A slit is cut at 4 cm from this same junction (utilizing a 8 cm length of ileum). 20 ml of warm Dulbecco's phosphate buffered saline, pH 6.5 (PBS) is used to flush out the intestine segment. The distal opening is cannulated with a 20 cm length of silicone tubing (0.02″ I.D.×0.037″ O.D.). The proximal cannulae is hooked up to a peristaltic pump and the intestine is washed for 20 min with warm PBS at 0.25 ml/min. Temperature of the gut segment is monitored continuously. At the start of the experiment, 2.0 ml of control sample ([¹⁴C]-taurocholate @ 0.05 mi/ml with 5 mM cold taurocholate) is loaded into the gut segment with a 3 ml syringe and bile sample collection is begun. Control sample is infused at a rate of 0.25 ml/min for 21 min. Bile samples fractions are collected every 3 minute for the first 27 minutes of the procedure. After the 21 min of sample infusion, the ileal loop is washed out with 20 ml of warm PBS (using a 30 ml syringe), and then the loop is washed out for 21 min with warm PBS at 0.25 ml/min. A second perfusion is initiated as described above but this with test compound being administered as well (21 min administration followed by 21 min of wash out) and bile sampled every 3 min for the first 27 min. If necessary, a third perfusion is performed as above that typically contains the control sample.

Measurement of Hepatic Cholesterol Concentration (HEPATIC CHOL)

Liver tissue was weighed and homogenized in chloroform:methanol (2:1). After homogenization and centrifugation the supernatant was separated and dried under nitrogen. The residue was dissolved in isopropanol and the cholesterol content was measured enzymatically, using a combination of cholesterol oxidase and peroxidase, as described by Allain, C. A., et al. (1974) Clin. Chem. 20, 470.

Measurement of Hepatic EMG CoA-Reductase Activity (HMG COA)

Hepatic microsomes were prepared by homogenizing liver samples in a phosphate/sucrose buffer, followed by centrifugal separation. The final pelleted material was resuspended in buffer and an aliquot was assayed for HMG CoA reductase activity by incubating for 60 minutes at 37° C. in the presence of ¹⁴C-HMG-CoA (Dupont-NEN). The reaction was stopped by adding 6N HCl followed by centrifugation. An aliquot of the supernatant was separated, by thin-layer chromatography, and the spot corresponding to the enzyme product was scraped off the plate, extracted and radioactivity was determined by scintillation counting. (Reference: Akerlund, J. and Bjorkhem, I. (1990) J. Lipid Res. 31, 2159).

Determination of Serum Cholesterol (SER.CHOL, HDL-CHOL, TGI and VLDL+LDL)

Total serum cholesterol (SER.CHOL) was measured enzymatically using a commercial kit from Wako Fine Chemicals (Richmond, Va.); Cholesterol C11, Catalog No. 276-64909. HDL cholesterol (HDL-CHOL) was assayed using this same kit after precipitation of VLDL and LDL with Sigma Chemical Co. HDL Cholesterol reagent, Catalog No. 352-3 (dextran sulfate method). Total serum triglycerides (blanked) (TGI) were assayed enzymatically with Sigma Chemical Co. GPO-Trinder, Catalog No. 337-B. VLDL and LDL (VLDL+LDL) cholesterol concentrations were calculated as the difference between total and HDL cholesterol.

Measurement of Hepatic Cholesterol 7-α-Hydroxylase Activity (7a-OHase)

Hepatic microsomes were prepared by homogenizing liver samples in a phosphate/sucrose buffer, followed by centrifugal separation. The final pelleted material was resuspended in buffer and an aliquot was assayed for cholesterol 7-α-hydroxylase activity by incubating for 5 minutes at 37° C. in the presence of NADPH. Following extraction into petroleum ether, the organic solvent was evaporated and the residue was dissolved in acetonitrile/methanol. The enzymatic product was separated by injecting an aliquot of the extract onto a C₁₈ reversed phase HPLC column and quantitating the eluted material using UV detection at 240 nm. (Reference: Horton, J. D., et al. (1994) J. Clin. Invest. 93, 2084).

Rat Gavage Assay

Male Wister rats (275-300 g) are administered IBAT inhibitors using an oral gavage procedure. Drug or vehicle (0.2% Tween 80 in water) is administered once a day (9:00-10:0 a.m.) for 4 days at varying dosages in a final volume of 2 mL per kilogram of body weight. Total fecal samples are collected during the final 48 hours of the treatment period and analyzed for bile acid content using an enzymatic assay as described below. Compound efficacy is determined by comparison of the increase in fecal bile acid (FBA) concentration in treated rats to the mean FBA concentration of rats in the vehicle group.

Measurement of Fecal Bile Acid Concentration (FBA)

Total fecal output from individually housed hamsters was collected for 24 or 48 hours, dried under a stream of nitrogen, pulverized and weighed. Approximately 0.1 gram was weighed out and extracted into an organic solvent (butanol/water). Following separation and drying, the residue was dissolved in methanol and the amount of bile acid present was measured enzymatically using the 3α-hydroxysteroid steroid dehydrogenase reaction with bile acids to reduce NAD. (Reference: Mashige, F., et al. (1981) Clin. Chem. 27, 1352).

[³H]taurocholate Uptake in Rabbit Brush Border Membrane Vesicles (BBMV)

Rabbit Ileal brush border membranes were prepared from frozen ileal mucosa by the calcium precipitation method describe by Malathi et al. (Reference: (1979) Biochimica Biophysica Acta, 554, 259). The method for measuring taurocholate was essentially as described by Kramer et al. (Reference: (1992) Biochimica Biophysica Acta, 1111, 93) except the assay volume was 200 μl instead of 100 μl. Briefly, at room temperature a 190 μl solution containing 2 μM [³H]-taurocholate(0.75 μCi), 20 mM tris, 100 mM NaCl, 100 mM mannitol pH 7.4 was incubated for 5 sec with 10 μl of brush border membrane vesicles (60-120 μg protein). The incubation was initiated by the addition of the BBMV while vortexing and the reaction was stopped by the addition of 5 ml of ice cold buffer (20 mM Hepes-tris, 150 mM KCl) followed immediately by filtration through a nylon filter (0.2 μm pore) and an additional 5 ml wash with stop buffer.

Acyl-CoA;cholesterol Acyl Transferase (ACAT)

Hamster liver and rat intestinal microsomes were prepared from tissue as described previously (Reference: (1980) J. Biol. Chem. 255, 9098) and used as a source of ACAT enzyme. The assay consisted of a 2.0 ml incubation containing 24 μM Oleoyl-CoA (0.05 μCi) in a 50 mM sodium phosphate, 2 mM DTT ph 7.4 buffer containing 0.25% BSA and 200 μg of microsomal protein. The assay was initiated by the addition of oleoyl-CoA. The reaction went for 5 min at 37° C. and was terminated by the addition of 8.0 ml of chloroform/methanol (2:1). To the extraction was added 125 μg of cholesterol oleate in chloroform methanol to act as a carrier and the organic and aqueous phases of the extraction were separated by centrifugation after thorough vortexing. The chloroform phase was taken to dryness and then spotted on a silica gel 60 TLC plate and developed in hexane/ethyl ether (9:1). The amount of cholesterol ester formed was determined by measuring the amount of radioactivity incorporated into the cholesterol oleate spot on the TLC plate with a Packard instaimager.

Data from each of the noted compounds in the assays described above is as set forth in TABLES 5, 6, 7, and 8 as follows:

TABLE 5 In vitro % % Inhibition Inhibition % of Control of TC of Alanine Transport of TC in COMPOUND IC50 uM* Uptake @ 100 uM# Update @ 100 uM# Rat Ileum @ 0.1 mM# Benzothiazepine=  2 0  45.4 +/− 0.7  12 25  3  0  4a  3  5a 34  5b 40 0  72.9 ± 5.4 @ 0.5 mM  4b  9 18  6  14b 18  14a 13 13 23 15 60  19a  0  19b 15  8a 41 Mixture of 69 8a and 8b Mixture of  6 9a and 9b  6a  5  6b 85  9a  5  0% @ 25 μM 53.7 +/− 3.9  Mixture of 13 6a and 20 Mixture of   0.8 14% @ 25 μM 6d and 10a  21a 37  21c 52  21b 45  6c  2 58.5 68.8 +/− 5.7 at 0.4 mM   6d   0.6 77.7 16.1 +/− 1.1 @ 0.5 mM  30.2 +/− 0.9 @ 0.15 mM 17 10  7 50 49.3  10a  7 77.6 62.4 =/− 2.5 @ 0.2 mM  10b 15 68.6 25   0.1  4% @ 10 μM 26.0 +/− 3.3  26  2 31% @ 25 μM 87.9 +/− 1.5  27  5  7% @ 20 μM 28  8 31% @ 20 μM 29 88 @ 50 μM 30 96 @ 50 μM 31 41 @ 50 μM 37  3  0% @ 5 μM  38   0.3 11% @ 5 μM  20.6 +/− 5.7  40 49 @ 50 μM 41  2  0% @ 20 μM 42   1.5 43   1.5 16% @ 25 μM 48  2 22% @ 20 μM 49    0.15  21% @ 200 μM 21.2 +/− 2.7  57 51 @ 50 μM 58 20 @ 50 μM 59 70 60  9 59   61 30 175   62 10 63 90 @ 6 μM  64 100 @ 6 μM  *In vitro Taurocholate Cell Uptake #Unless otherwise noted =Comparative Example is Example No. 1 in WO 93/16055

TABLE 6 TC-uptake TC-uptake TC-uptake ACAT ACAT (H14 cells) Ileal Loop (BBMV) (liver) intestine Compound IC(50) EC(50) IC(50) IC(50) IC(50) COMP.   1 μM 74 μM   3 μM 20 μM 20 μM EXAMPLE* 6d 0.6 μM 31 μM 1.5 μM 25 μM 20 μM *38  0.3 μM 12 μM   2 μM 15 μM N.D. 49 0.1 μM 12 μM N.D.  6 μM N.D. 25 0.1 μM 20 μM 0.8 μM  8 μM  8 μM

Comparative Example is Example No. 1 in WO 93/16055

TABLE 7 EFFICACY OF COMPOUND NO. 25 IN CHOLESTEROL-FED HAMSTERS PARAMETER CONTROL 4% CHOLESTYRAMINE 0.2% CPD. NO. 25 WEIGHT (G) (mean ± SEM, *p < 0.05, A-Student's t, B-Dunnett's) day 1 117 (2) 114 (6) 117 (5) day 14 127 (3) 127 (3) 132 (4) LIVER WEIGHT (G) 5.4 (0.3) 4.9 (0.4) 5.8 (0.2) SER. CHOL (mg %) 143 (7) 119 (4)*A,B 126 (2)*A,B HDL-CHOL (mg %) 89 (4) 76 (3)*A,B 76 (1)*A,B VLDL + LDL 54 (7) 42 (3)*A 50 (3) TGI (mg %) 203 (32) 190 (15) 175 (11) HEPATIC CHOL (mg/g) 2.5 (0.3) 1.9 (0.1)*A,B 1.9 (0.1)*A,B HMG COA (pm/mg/min.) 15.8 (7.6) 448.8 (21.6)*A,B 312.9 (37.5)*A,B 7a-OHase (pm/mg/min.) 235.3 (25.1) 24 HR. FECAL Wt (G) 357.2 (28.3)*A,B 291.0 (6.0)*A FBA (mM/24 H/100 g) 2.3 (0.1) 2.4 (0.04) 6.2 (0.8) 2.7 (0.1)*A,B 11.9 (0.5)*A,B 12.3 (1.5)*A,B

TABLE 8 EFFICACY OF COMPOUND NO. 25 IN RAT ALZET MINIPUMP MODEL 20 MPL/DAY CONTROL CPD. NO. 25 PARAMETER (mean ± SEM, *p < 0.05, WEIGHT (G) A-Student's t, B-Dunnett's) day 1 307 (4) 307 (3) day 8 330 (4) 310 (4)*A,B LIVER WEIGHT (G) 15.5 (0.6) 14.6 (0.4) SER. CHOL (mg %) 85 (3) 84 (3) HEPATIC CHOL (mg/g) 21 (0.03) 2.0 (0.03) HMG COA pm/mg/min 75.1 (6.4) 318.0 (40.7)*A,B 7a-OHase (pm/mg/min) 281.9 (13.9) 535.2 (35.7)*A,B 24 HR. FECAL WT (G) 5.8 (0.1) 5.7 (0.4) FBA (mM/24 H/100 g) 17.9 (0.9) 39.1 (4.5)*A,B

Additional in vitro taurocholate uptake tests were conducted in the following compounds listed in Table 9.

TABLE 9 Biological Data for Some Compounds of the Present Invention Human TC Alanine Uptake Compound IC₅₀ Percent Number (μM) Inhibition @ μM  101   0 @ 1.0  102 0.083  103   13 @ 0.25  104 0.0056  105 0.6  106 0.8  107  14.0 @ 0.063  108 0.3  109  2.0 @ 0.063  110 0.09  111 2.5  112 3.0  113 0.1  114 0.19  115 8.0  116 0.3  117  12.0 @ 0.625  118 0.4  119 1.3  120 34.0 @ 5.0   121 0.068  122 1.07  123 1.67  124 14.0 @ 6.25  125 18.0  126   18 @ 1.25  127 0.55  128 0.7  129 0.035  131 1.28  132  5.4 @ 0.063  133 16.0  134 0.3  135 22.0  136 0.09  137 2.4  138 3.0  139 >25.0  140  141  142 0.5  143 0.03  144 0.053  262 0.07  263 0.7  264 0.2  265 2.0  266 0.5  267 0.073  268 0.029  269 0.08  270 0.12  271 0.07  272 0.7  273 1.9  274 0.18  275  5.0 @ 0.25  276 0.23  277 0.04  278 3.0  279 0.4  280 0.18  281 0.019  282 0.021  283 0.35  284 0.08  285  286 19.0  287 4.0  288 10.0 @ 6.25  289 0.23  290 0.054  291 0.6  292 0.046  293 1.9  294 0.013  295 1.3  296 1.6 1000 1001 1002 1003 1004 1005 0.0004 1006 0.001 1007 0.001 1008 0.001 1009 0.001 1010 0.001 1011 0.001 1012 0.0015 1013 0.002 1014 0.002 1015 0.002 1016 0.002 1017 0.002 1018 0.002 1019 0.002 1020 0.002 1021 0.002 1022 0.002 1023 0.002 1024 0.002 1025 0.002 1026 0.002 1027 0.002 1028 0.002 1029 0.002 1030 0.002 1031 0.002 1032 0.002 1033 0.002 1034 0.002 1035 0.002 1036 0.002 1037 0.0022 1038 0.0025 1039 0.0026 1040 0.003 1041 0.003 1042 0.003 1043 0.003 1044 0.003 1045 0.003 1046 0.003 1047 0.003 1048 0.003 1049 0.003 1050 0.003 1051 0.003 1052 0.003 1053 0.003 1054 0.003 1055 0.003 1056 0.003 1057 0.003 1058 0.003 1059 0.003 1060 0.0036 1061 0.004 1062 0.004 1063 0.004 1064 0.004 1065 0.004 1066 0.004 1067 0.004 1068 0.004 1069 0.004 1070 0.004 1071 0.004 1072 0.004 1073 0.004 1074 0.004 1075 0.0043 1076 0.0045 1077 0.0045 1078 0.0045 1079 0.005 1080 0.005 1081 0.005 1082 0.005 1083 0.005 1084 0.005 1085 0.005 1086 0.005 1087 0.005 1088 0.0055 1089 0.0057 1090 0.006 1091 0.006 1092 0.006 1093 0.006 1094 0.006 1095 0.006 1096 0.006 1097 0.006 1098 0.006 1099 0.0063 1100 0.0068 1101 0.007 1102 0.007 1103 0.007 1104 0.007 1105 0.007 1106 0.0073 1107 0.0075 1108 0.0075 1109 0.008 1110 0.008 1111 0.008 1112 0.008 1113 0.009 1114 0.009 1115 0.0098 1116 0.0093 1117 0.01 1118 0.01 1119 0.01 1120 0.01 1121 0.01 1122 0.011 1123 0.011 1124 0.011 1125 0.012 1126 0.013 1127 0.013 1128 0.017 1129 0.018 1130 0.018 1131 0.02 1132 0.02 1133 0.02 1134 0.02 1135 0.021 1136 0.021 1137 0.021 1138 0.022 1139 0.022 1140 0.023 1141 0.023 1142 0.024 1143 0.027 1144 0.028 1145 0.029 1146 0.029 1147 0.029 1148 0.03 1149 0.03 1150 0.03 1151 0.031 1152 0.036 1153 0.037 1154 0.037 1155 0.039 1156 0.039 1157 0.04 1158 0.06 1159 0.06 1160 0.062 1161 0.063 1162 0.063 1163 0.09 1164 0.093 1165 0.11 1166 0.11 1167 0.12 1168 0.12 1169 0.12 1170 0.13 1171 0.14 1172 0.14 1173 0.15 1174 0.15 1175 0.17 1176 0.18 1177 0.18 1178 0.19 1179 0.19 1180 0.2 1181 0.22 1182 0.25 1183 0.28 1184 0.28 1185 0.28 1186 0.3 1187 0.32 1188 0.35 1189 0.35 1190 0.55 1191 0.65 1192 1.0 1193 1.0 1194 1.6 1195 1.7 1196 2.0 1197 2.2 1198 2.5 1199 4.0 1200 6.1 1201 8.3 1202 40.0 1203    0 @ 0.063 1204 0.05 1205 0.034 1206 0.035 1207 0.068 1208 0.042 1209    0 @ 0.063 1210 0.14 1211 0.28 1212 0.39 1213 1.7 1214 0.75 1215 0.19 1216 0.39 1217 0.32 1218 0.19 1219 0.34 1220 0.2 1221 0.041 1222 0.065 1223 0.28 1224 0.33 1225 0.12 1226 0.046 1227 0.25 1228 0.038 1229 0.049 1230 0.062 1231 0.075 1232 1.2 1233 0.15 1234 0.067 1235 0.045 1236 0.05 1237 0.07 1238 0.8 1239 0.035 1240 0.016 1241 0.047 1242 0.029 1243 0.63 1244 0.062 1245 0.32 1246 0.018 1247 0.017 1248 0.33 1249 10.2 1250 0.013 1251 0.62 1252 29. 1253 0.3 1254 0.85 1255 0.69 1256 0.011 1257 0.1 1258 0.12 1259 16.5 1260 0.012 1261 0.019 1262 0.03 1263 0.079 1264 0.21 1265 0.24 1266 0.2 1267 0.29 1268 0.035 1269 0.026 1270 0.026 1271 0.011 1272 0.047 1273 0.029 1274 0.028 1275 0.024 1276 0.029 1277 0.018 1278 0.017 1279 0.028 1280 0.76 1281 0.055 1282 0.17 1283 0.17 1284 0.011 1285 0.027 1286 0.068 1287 0.071 1288 0.013 1289 0.026 1290 0.017 1291 0.013 1292 0.025 1293 0.019 1294 0.011 1295 0.014 1296 0.063 1297 0.029 1298 0.018 1299 0.012 1300 1.0 1301 0.15 1302 1.4 1303 0.26 1304 0.25 1305 0.25 1306 1.2 1307 3.1 1308 0.04 1309 0.24 1310 1.16 1311 3.27 1312 5.0 1313 6.1 1314 0.26 1315 1.67 1316 3.9 1317 21.0 1318 1319 11.0 @ 0.25 1320 1321 11.1 @ 5.0  1322   3.0 @ 0.0063 1323   4.0 @ 0.0063 1324  43.0 @ 0.0008 1325   1.0 @ 0.0063 1326  36.0 @ 0.0008 1327   3.0 @ 0.0063 1328  68.0 @ 0.0063 1329   2.0 @ 0.0063 1330   9.0 @ 0.0063 1331  57.0 @ 0.0008 1332  43.0 @ 0.0008 1333    0 @ 0.0063 1334  50.0 @ 0.0008 1335  38.0 @ 0.0008 1336  45.0 @ 0.0008 1337    0 @ 0.0063 1338  1.0 @ 0.25 1339    0 @ 0.063 1340  9.0 @ 0.063 1341  1.0 @ 0.063 1342  1.0 @ 0.063 1343 1344 1345 13.0 @ 0.25 1346 1347 0.0036 1348 1349 1350 1351 0.44 1352 0.10 1353 0.0015 1354 0.006 1355 0.0015 1356 0.22 1357 0.023 1358 0.008 1359 0.014 1360 0.003 1361 0.004 1362 0.019 1363 0.008 1364 0.006 1365 0.008 1366 0.015 1367 0.002 1368 0.005 1369 0.005 1370 0.002 1371 0.004 1372 0.004 1373 0.008 1374 0.007 1375 0.002 1449 0.052 1450 0.039 1451 0.014

Additional in vitro taurocholate uptake tests and in vivo rat gavage tests were conducted on the following compounds listed in Tables 10 and 11.

TABLE 10 In Vitro Taurocholate Uptake Assay Data for Some Additional Compounds of the Present Invention Compound of Human TC IC50 Example Number (nM) 1402 25 1403 23 1404 10 1405 21 1406 4 1407 3 1408 1 1409 0.9 1410 2 1411 2 1412 3 1413 3 1414 15 1415 2 1416 14 1417 2 1418 <1 1419 3 1420 11 1421 4 1422 3 1423 3 1424 14 1425 2 1426 0.3 1427 2 1428 0.7 1429 1430 3 1431 5 1432 26 1433 67

TABLE 11 Rat Gavage Assay Data for Some Additional Compounds of the Present Invention Delta (micromoles Compound of Dose fecal bile Example No. Study No. (mg/kg/day) acid per day) 1402 28 5 58.2 .2 1.3 .04 0.3 1402 30 2 50.3 .4 40.9 .08 48.5 .016 22.9 1403 30 2 41.6 .4 35.2 .08 11.9 .016 3 1404 28 5 93.7 .2 59.1 .04 33.5 1406 32 2 47.8 .4 31.6 .08 12.8 .016 −8.5 1407 32 2 51.9 .4 30.1 .08 27.5 .016 6.4 1407 33 2 35 .4 12.7 .08 −.04 .016 −4.5 1408 29 2 41.2 .4 36.8 .08 16.8 .016 −3.3 1408 37 2 26.2 .4 45.2 .08 26.3 .016 6.6 1409 33 2 19.2 .4 28.7 .08 14.1 .016 −1.7 1409 41 2 44.2 .4 35.9 .08 14.5 .016 11 1410 33 32.4 34.3 27.9 9.3 1410 35 2 26.2 .4 36.5 .08 18.5 .016 20.4 1411 34 2 63.4 .4 54.1 .08 33 .016 22.3 1413 26 5 52.3 .2 42.4 .04 19 1414 27 5 45.2 .2 39.5 .04 14.3 1414 31 2 41.5 .4 33.7 .08 29 .016 3.8 1415 28 5 59.9 .2 48.1 .04 23.9 1415 37 2 48.9 .4 25.7 .08 27.1 .016 12.7 1416 29 2 46.1 .4 21.9 .08 25 .016 −7.8 1417 31 2 51.4 .4 42 .08 39.6 .016 29.3 1418 29 2 20.3 .4 29.5 .08 −4.6 .016 −10 1419 31 2 28.5 .4 13.9 .08 10.3 .016 5.8 1420 31 2 53.1 .4 45 .08 38.1 .016 29.6 1421 32 2 57.8 .4 27.7 .08 25.3 .016 4.7 1423 34 2 56.5 .4 69.3 .08 35.3 .016 14.4 1425 21 5 91.8 .2 100. .04 66.4 1425 30 2 44.6 .4 62 .08 69.5 .016 31.6 1425 40 2 48.3 .4 45 .08 31.2 .016 30 1426 33 2 52.4 .4 19.5 .08 23.1 .016 24.6 1426 35 2 37.7 .4 41.7 .08 40.5 .016 24.6 1426 39 2 54.3 .4 48.7 .08 51.8 .016 26.8 1426 43 2 40.8 .4 21.7 .08 5.9 .016 4.1 1427 40 2 36.7 .4 35.8 .08 27.3 .016 13.8 1428 34 2 40.4 .4 64.9 .08 24.4 .016 12.2 1428 42 2 46 .4 40.7 .08 26 .016 1.1 1429 41 2 34.5 .4 24.9 .08 18.7 .016 9.2 1429 42 2 47.1 .4 31.1 .08 35.5 .016 4.8 1430 30 2 51.2 .4 50.4 .08 20.7 .016 −5.6 1431 32 28.3 45.8 21.9 1.1 1432 28 5 36.2 .2 9.7 .04 2.4 1433 24 20 66.5 2 47.4 .2 26.5

The examples herein can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.

Novel compositions of the invention are further illustrated in attached Exhibits A and B.

The invention being thus described, it is apparent that the same can be varied in many ways. Such variations are not to be regarded as a departure from the spirit and scope of the present invention, and all such modifications and equivalents as would be obvious to one skilled in the art are intended to be included within the scope of the following claims.

TABLE C2 Exhibit A Alternative Compounds #2 (Families F101-F123)

Cpd Family # R¹ = R² R⁵ (R^(x))q F101 CHOSEN Ph— CHOSEN FROM FROM TABLE 1 TABLE 1 F102 CHOSEN p-F—Ph— CHOSEN FROM FROM TABLE 1 TABLE 1 F103 CHOSEN m-F—Ph— CHOSEN FROM FROM TABLE 1 TABLE 1 F104 CHOSEN p-CH₃O—Ph— CHCSEN FROM FROM TABLE 1 TABLE 1 F105 CHOSEN m-CH₃O—Ph— CHOSEN FROM FROM TABLE 1 TABLE 1 F106 CHOSEN p-(CH₃)₂N—Ph— CHOSEN FROM FROM TABLE 1 TABLE 1 F107 CHOSEN m-(CH₃)₂N—Ph CHOSEN FROM FROM TABLE 1 TABLE 1 F108 CHOSEN I⁻, p-(CH₃)₃—N⁺—Ph— CHOSEN FROM FROM TABLE 1 TABLE 1 F109 CHOSEN I⁻, m-(CH₃)₃—N⁺—Ph— CHOSEN FROM FROM TABLE 1 TABLE 1 F110 CHOSEN I⁻, p-(CH₃)₃—N⁺—CH₂CH₂— CHOSEN FROM (OCH₂CH₂)₂—O—Ph— FROM TABLE 1 TABLE 1 F111 CHOSEN I⁻, m-(CH₃)₃—N⁺—CH₂CH₂— CHOSEN FROM (OCH₂CH₂)₂—O—Ph— FROM TABLE 1 TABLE 1 F112 CHOSEN I⁻, p-(N,N- CHOSEN FROM dimethylpiperazine)-(N′ )- FROM TABLE 1 CH₂—(OCH₂CH₂)₂—O—Ph— TABLE 1 F113 CHOSEN I⁻, m-(N,N- CHOSEN FROM dimethylpiperazine)-(N′)- FROM TABLE 1 CH₂—(OCH₂CH₂)₂—O—Ph— TABLE 1 F114 CHOSEN m-F—Ph— CHOSEN FROM p-CH₃O- FROM TABLE 1 TABLE 1 F115 CHOSEN 3,4,dioxy-methylene-Ph— CHOSEN FROM FROM TABLE 1 TABLE 1 F116 CHOSEN m-F—Ph— CHOSEN FROM p-F—Ph— FROM TABLE 1 TABLE 1 F117 CHOSEN m-CH₃O— CHOSEN FROM p-F—Ph— FROM TABLE 1 TABLE 1 F118 CHOSEN 4-pyridine CHOSEN FROM FROM TABLE 1 TABLE 1 F119 CHOSEN N-methyl-4-pyridinium CHOSEN FROM FROM TABLE 1 TABLE 1 F120 CHOSEN 3-pyridine CHOSEN FROM FROM TABLE 1 TABLE 1 F121 CHOSEN N-methyl-3-pyridinium CHOSEN FROM FROM TABLE 1 TABLE 1 F122 CHOSEN 2-pyridine CHOSEN FROM FROM TABLE 1 TABLE 1 F123 CHOSEN p-CH₃O₂C—Ph— CHOSEN FROM FROM TABLE 1 TABLE 1

Similar families can be generated where R¹ is not equal to R², such as R¹=Et and R²=n-Bu, but (R^(x))q is chosen from table C1. 

What is claimed is:
 1. An oral pharmaceutical composition comprising a compound of formula (I):

wherein: q is an integer from 1 to 4; n is an integer from 0 to 2; R¹ and R² are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl, wherein alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl optionally are substituted with one or more substituents selected from the group consisting of OR⁹, NR⁹R¹⁰, N⁺R⁹R¹⁰R^(w)A⁻, SR⁹, S⁺R⁹R¹⁰A⁻, P⁺R⁹R¹⁰R¹¹A⁻, S(O)R⁹, SO₂R⁹, SO₃R⁹, CO₂R⁹, CN, halogen, oxo, and CONR⁹R¹⁰, wherein alkyl, alkenyl, alkynyl, alkylaryl, alkoxy, alkoxyalkyl, (polyalkyl)aryl, and cycloalkyl optionally have one or more carbons replaced by O, NR⁹, N⁺R⁹R¹⁰A—, S, SO, SO₂, S⁺R⁹A⁻, P⁺R⁹R¹⁰A⁻, or phenylene, wherein R⁹, R¹⁰, and R^(w) are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, arylalkyl, and alkylammoniumalkyl; or R¹ and R² taken together with the carbon to which they are attached form C₃-C₁₀ cycloalkyl; R³ and R⁴ are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, acyloxy, aryl, heterocycle, OR⁹, NR⁹R¹⁰, SR⁹, S(O)R⁹, SO₂R⁹, and SO₃R⁹, wherein R⁹ and R¹⁰ are as defined above; or R³ and R⁴ together form ═O, ═NOR¹¹, ═S, ═NNR¹¹R¹², ═NR⁹, or ═CR¹¹R¹², wherein R¹¹ and R¹² are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl, OR⁹, NR⁹R¹⁰, SR⁹, S(O)R⁹, SO₂R⁹, SO₃R⁹, CO₂R⁹, CN, halogen, oxo, and CONR⁹R¹⁰, wherein R⁹ and R¹⁰ are as defined above, provided that both R³ and R⁴ cannot be OH, NH₂, and SH, or R¹¹ and R¹² together with the nitrogen or carbon atom to which they are attached form a cyclic ring; R⁵ and R⁶ are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, OR³⁰, SR⁹, S(O)R⁹, SO₂R⁹, and SO₃R⁹, wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, and quaternary heteroaryl can be substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, halogen, oxo, OR¹³, NR¹³R¹⁴, SR¹³, S(O)R¹³, SO₂R¹³, SO₃R¹³, NR¹³OR¹⁴, NR¹³NR¹⁴R¹⁵, NO₂, CO₂R¹³, CN, OM, SO₂OM, SO₂NR¹³R¹⁴, C(O)NR¹³R¹⁴, C(O)OM, COR¹³, P(O)R¹³R¹⁴, P⁺R¹³R¹⁴R¹⁵A⁻, P(OR¹³)OR¹⁴, S⁺R¹³R¹⁴A⁻, and N⁺R⁹R¹¹R¹²A⁻,  wherein: A⁻ is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation, said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can be further substituted with one or more substituent groups selected from the group consisting of OR⁷, NR⁷R⁸, SR⁷, S(O)R⁷, SO₂R⁷, SO₃R⁷, CO₂R⁷, CN, oxo, CONR⁷R⁸, N⁺R⁷R⁸R⁹A—, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, P(O)R⁷R⁸, P⁺R⁷R⁸R⁹A⁻, and P(O)(OR⁷)OR⁸, and wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can optionally have one or more carbons replaced by O, NR⁷, N⁺R⁷R⁸A—, S, SO, SO₂, S⁺R⁷A—, PR⁷, P(O)R⁷, P⁺R⁷R⁸A—, or phenylene, and R¹³, R¹⁴, and R¹⁵ are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, aryl, arylalkyl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, and quaternary heteroarylalkyl, wherein alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, and polyalkyl optionally have one or more carbons replaced by O, NR⁹, N⁺R⁹R¹⁰A—, S, SO, SO₂, S⁺R⁹A⁻, PR⁹, P⁺R⁹R¹⁰A—, P(O)R⁹, phenylene, carbohydrate, amino acid, peptide, or polypeptide, and R¹³, R¹⁴, and R¹⁵ are optionally substituted with one or more groups selected from the group consisting of sulfoalkyl, quaternary heterocycle, quaternary heteroaryl, OR⁹, NR⁹R¹⁰, N⁺R⁹R¹¹R¹²A⁻, SR⁹, S(O)R⁹, SO₂R⁹, SO₃R⁹, oxo, CO₂R⁹, CN, halogen, CONR⁹R¹⁰, SO₂OM, SO₂NR⁹R¹⁰, PO(OR¹⁶)OR¹⁷, P⁺R⁹R¹⁰R¹¹A—, S⁺R⁹R¹⁰A—, and C(O)OM, wherein R¹⁶ and R¹⁷ are independently selected from the substituents constituting R⁹ and M; or R¹⁴ and R¹⁵, together with the nitrogen atom to which they are attached, form a cyclic ring; and R³⁰ is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, alkylammoniumalkyl, and arylalkyl; and R⁷ and R⁸ are independently selected from the group consisting of hydrogen and alkyl; and one or more R^(x) are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, polyalkyl, acyloxy, aryl, arylalkyl, halogen, haloalkyl, cycloalkyl, heterocycle, heteroaryl, polyether, quaternary heterocycle, quaternary heteroaryl, OR¹³, NR¹³R¹⁴, SR¹³, S(O)R¹³, S(O)₂R¹³, SO₃R¹³, SO⁺R¹³R¹⁴A—, NR¹³OR¹⁴, NR¹³NR¹⁴R¹⁵, NO₂, CO₂R¹³, CN, OM, SO₂OM, SO₂NR¹³R¹⁴, NR¹⁴C(O)R¹³, C(O)NR¹³R¹⁴, NR14C(O)R13, C(O)OM, COR¹³, OR¹⁸, S(O)_(n)NR¹⁸, NR¹³R¹⁸, NR¹⁸OR¹⁴, N⁺R⁹R¹¹R¹²A⁻, P⁺R⁹R¹¹R¹²A⁻, amino acid, peptide, polypeptide, and carbohydrate, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, polyalkyl, heterocycle, acyloxy, arylalkyl, haloalkyl, polyether, quaternary heterocycle, and quaternary heteroaryl can be further substituted with OR⁹, NR⁹R¹⁰, N⁺R⁹R¹¹R¹²A⁻, SR⁹, S(O)R⁹, SO₂R⁹, SO₃R⁹, oxo, CO₂R⁹, CN, halogen, CONR⁹R¹⁰, SO₂OM, SO₂NR⁹R¹⁰, PO(OR¹⁶)OR¹⁷, P⁺R⁹R¹¹R¹²A⁻, S⁺R⁹R¹⁰A⁻, or C(O)OM, and wherein R¹⁸ is selected from the group consisting of acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, wherein acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, quaternary heterocycle, and quaternary heteroaryl optionally are substituted with one or more substituents selected from the group consisting of OR⁹, NR⁹R¹⁰, N⁺R⁹R¹¹R¹²A⁻, SR⁹, S(O)R⁹, SO₂R⁹, SO₃R⁹, oxo, CO₂R⁹, CN, halogen, CONR⁹R¹⁰, SO₃R⁹, SO₂OM, SO₂NR⁹R¹⁰, PO(OR¹⁶)OR¹⁷, and C(O)OM, wherein in R^(x), one or more carbons are optionally replaced by O, NR¹³, N⁺R¹³R¹⁴A—, S, SO, SO₂, SO⁺R¹³A⁻, PR¹³, P(O)R¹³, P⁺R¹³R¹⁴A—, phenylene, amino acid, peptide, polypeptide, carbohydrate, polyether, or polyalkyl, wherein in said polyalkyl, phenylene, amino acid, peptide, polypeptide, and carbohydrate, one or more carbons are optionally replaced by O, NR⁹, N⁺R⁹R¹⁰A⁻, S, SO, SO₂, S⁺R⁹A—, PR⁹, P⁺R⁹R¹⁰A—, or P(O)R⁹; wherein quaternary heterocycle and quaternary heteroaryl are optionally substituted with one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR¹³, NR¹³R¹⁴, SR¹³, S(O)R¹³, SO₂R¹³, SO₃R¹³, NR¹³OR¹⁴, NR¹³NR¹⁴R¹⁵, NO₂, CO₂R¹³, CN, OM, SO₂OM, SO₂NR¹³R¹⁴, C(O)NR¹³R¹⁴, C(O)OM, COR¹³, P(O)R¹³R¹⁴, P⁺R¹³R¹⁴R¹⁵A⁻, P(OR¹³)OR¹⁴, S⁺R¹³R¹⁴A⁻, and N⁺R⁹R¹¹R¹²A⁻, provided that both R⁵ and R⁶ cannot be hydrogen or SH; provided that when R⁵ or R⁶ is phenyl, only one of R¹ or R² is H; provided that when q=1 and R^(x) is styryl, anilido, or anilinocarbonyl, only one of R⁵ or R⁶ is alkyl; or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a pharmaceutically acceptable carrier suitable for delivery of said compound of formula (I) to the small intestine by oral administration.
 2. The oral pharmaceutical composition of claim 1 wherein said pharmaceutically acceptable carrier is suitable for delivering said compound of formula (I) to the ileum.
 3. The oral pharmaceutical composition of claim 2 wherein said pharmaceutical composition is a pH sensitive release formulation.
 4. The oral pharmaceutical composition of claim 2 wherein said pharmaceutical composition is a bioadhesive formulation.
 5. The oral pharmaceutical composition of claim 2 wherein release of said compound of formula (I) is accomplished by enzymatic action.
 6. The oral pharmaceutical composition of claim 2 provided in a solid dosage form.
 7. The oral pharmaceutical composition of claim 6 wherein said solid dosage form comprises a tablet optionally coated with an enteric coating.
 8. The oral pharmaceutical composition of claim 7 wherein said enteric coating comprises a member selected from the group consisting of cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropylmethylcellulose phthalate, and anionic polymers of methacrylic acid and methacrylic acid methyl ester.
 9. The oral pharmaceutical composition of same 6 wherein said solid dosage form comprises a capsule optionally comprising an enteric coating.
 10. The oral pharmaceutical composition of claim 9 wherein said enteric coating comprises a member selected from the group consisting of cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropylmethylcellulose phthalate, and anionic polymers of methacrylic acid and methacrylic acid methyl ester.
 11. The oral pharmaceutical composition of claim 2 wherein said compound of formula (I) is provided in an amount from about 0.1 mg to about 100 mg.
 12. The oral pharmaceutical composition of claim 11 wherein said amount is from about 1 mg to about 75 mg.
 13. The oral pharmaceutical composition of claim 12 wherein said amount is from about 10 mg to about 50 mg.
 14. The oral pharmaceutical composition of claim 1, wherein R⁵ and R⁶ are independently selected from the group consisting of H, aryl, heterocycle, quaternary heterocycle, and quaternary heteroaryl, wherein said aryl, heteroaryl, quaternary heterocycle, and quaternary heteroaryl can be substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR¹³, NR¹³R¹⁴, SR¹³, S(O)R¹³, SO₂R¹³, SO₃R¹³, NR¹³OR¹⁴, NR¹³NR¹⁴R¹⁵, NO₂, CO₂R¹³, CN, OM, SO₂OM, SO₂NR¹³R¹⁴, C(O)NR¹³R¹⁴, C(O)OM, COR¹³, P(O)R¹³R¹⁴, P⁺R¹³R¹⁴R¹⁵A⁻, P(OR¹³)OR¹⁴, S⁺R¹³R¹⁴A⁻, and N⁺R⁹R¹¹R¹²A⁻, wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can optionally have one or more carbons replaced by O, NR⁷, N⁺R⁷R⁸A⁻, S, SO, SO₂, S⁺R⁷A⁻, PR⁷, P(O)R⁷, P⁺R⁷R⁸A⁻, or phenylene, wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can be further substituted with one or more substituent groups selected from the group consisting of OR⁷, NR⁷R⁸, SR⁷, S(O)R⁷, SO₂R⁷, SO₃R⁷, CO₂R⁷, CN, oxo, CONR⁷R⁸, N⁺R⁷R⁸R⁹A—, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, P(O)R⁷R⁸, P⁺R⁷R⁸A⁻, and P(O)(OR⁷)OR⁸.
 15. The oral pharmaceutical composition of claim 14, wherein R⁵ or R⁶ has the formula —Ar—(R^(y))_(t) wherein: t is an integer from 0 to 5; Ar is selected from the group consisting of phenyl, thiophenyl, pyridyl, piperazinyl, piperonyl, pyrrolyl, naphthyl, furanyl, anthracenyl, quinolinyl, isoquinolinyl, quinoxalinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrimidinyl, thiazolyl, triazolyl, isothiazolyl, indolyl, benzoimidazolyl, benzoxazolyl, benzothiazolyl, and benzoisothiazolyl; and one or more R^(y) are independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR¹³, NR¹³R¹⁴, SR¹³, S(O)R¹³, SO₂R¹³, SO₃R¹³, NR¹³OR¹⁴, NR¹³NR¹⁴R¹⁵, NO₂, CO₂R¹³, CN, OM, SO₂OM, SO₂NR¹³R¹⁴, C(O)NR¹³R¹⁴, C(O)OM, COR¹³, P(O)R¹³R¹⁴, P⁺R¹³R¹⁴R¹⁵A⁻, P(OR¹³)OR¹⁴, S⁺R¹³R¹⁴A⁻, and N⁺R⁹R¹¹R¹²A⁻, wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can be further substituted with one or more substituent groups selected from the group consisting of OR⁷, NR⁷R⁸, SR⁷, S(O)R⁷, SO₂R⁷, SO₃R⁷, CO₂R⁷, CN, oxo, CONR⁷R⁸, N⁺R⁷R⁸R⁹A⁻, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, P(O)R⁷R⁸, P⁺R⁷R⁸A⁻, and P(O)(OR⁷)OR⁸, and wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can optionally have one or more carbons replaced by O, NR⁷, N⁺R⁷R⁸A⁻, S, SO, SO₂, S⁺R⁷A—, PR⁷, P(O)R⁷, P⁺R⁷R⁸A⁻, or phenylene.
 16. The oral pharmaceutical composition of claim 15, wherein R⁵ or R⁶ has the formula (II)


17. The oral pharmaceutical composition of claim 16, wherein n is 1 or
 2. 18. The oral pharmaceutical composition of claim 17, wherein one of R⁷ or R⁸ is H and the other of R⁷ or R⁸ is alkyl.
 19. The oral pharmaceutical composition of claim 17, wherein both R⁷ are R⁸ are H.
 20. The oral pharmaceutical composition of claim 17, wherein R¹ and R² are independently selected from the group consisting of H and alkyl.
 21. The oral pharmaceutical composition of claim 20, wherein said alkyl is a C₁-C₁₀ alkyl.
 22. The oral pharmaceutical composition of claim 20, wherein R¹ and R² are both alkyl.
 23. The oral pharmaceutical composition of claim 22, wherein said alkyl is a C₁-C₁₀ alkyl.
 24. The oral pharmaceutical composition of claim 23, wherein said alkyl is a C₂-C₇ alkyl.
 25. The oral pharmaceutical composition of claim 24, wherein said alkyl is a C₂-C₄ alkyl.
 26. The oral pharmaceutical composition of claim 25, wherein said alkyl is independently selected from the group consisting of ethyl, n-propyl, n-butyl, and isobutyl.
 27. The oral pharmaceutical composition of claim 20, wherein R¹ and R² are each n-butyl.
 28. The oral pharmaceutical composition of claim 20, wherein one of R¹ and R² is ethyl and the other of R¹ and R² is n-butyl.
 29. The oral pharmaceutical composition of claim 27, wherein q is 1, 2, or
 3. 30. The oral pharmaceutical composition of claim 28 wherein q is 1, 2, or
 3. 31. The oral pharmaceutical composition of claim 29, wherein q is 1 or
 2. 32. The oral pharmaceutical composition of claim 31, wherein q is
 1. 33. The oral pharmaceutical composition of claim 30, wherein q is 1 or
 2. 34. The oral pharmaceutical composition of claim 33, wherein q is
 1. 35. The oral pharmaceutical composition of claim 31, wherein and R³ and R⁴ are independently selected from the group consisting of H and OR⁹.
 36. The oral pharmaceutical composition of claim 33, wherein R³ and R⁴ are independently selected from the group consisting of H and OR⁹.
 37. The oral pharmaceutical composition of claim 35, wherein R⁹ is H.
 38. The oral pharmaceutical composition of claim 36, wherein R⁹ is H.
 39. The oral pharmaceutical composition of claim 37, wherein one or more R^(x) are in the 7-, 8-, or 9-position of the benzo ring of formula (I).
 40. The oral pharmaceutical composition of claim 38, wherein said R^(x) is in the 7-, 8-, or 9-position of the benzo ring of formula (I).
 41. The oral pharmaceutical composition of claim 39, wherein said R^(x) are in the 7- and 9-positions of the benzo ring of formula (I).
 42. The oral pharmaceutical composition of claim 40, wherein said R^(x) is in the 7-position of the benzo ring of formula (I).
 43. The oral pharmaceutical composition of claim 41, wherein said one or more R^(x) are independently selected from the group consisting of alkyl, aryl, cycloalkyl, heterocycle, polyalkyl, acyloxy, polyether, halogen, OR¹³, NR¹³R¹⁴, NR¹³NR¹⁴R¹⁵, N⁺R⁹R¹¹R¹²A⁻, SR¹³, S⁺R¹³R¹⁴, CO₂R¹³, NR¹⁴C(O)R¹³, and NR¹⁴C(O)R¹³, wherein alkyl, aryl, cycloalkyl, heterocycle, polyalkyl, acyloxy, and polyether, can be further substituted with OR⁹, NR⁹R¹⁰, N⁺R⁹R¹¹R¹²A⁻, SR⁹, S(O)R⁹, SO₂R⁹, SO₃R⁹, oxo, CO₂R⁹, CN, halogen, CONR⁹R¹⁰SO₂OM, SO₂NR⁹R¹⁰, PO(OR¹⁶)OR¹⁷, P⁺R⁹R¹¹R¹²A⁻, S⁺R⁹R¹⁰A⁻, or C(O)OM, and wherein in R^(x), one or more carbons are optionally replaced by O, NR¹³, N⁺R¹³R¹⁴A⁻, S, SO, SO₂, S⁺R¹³A—, PR¹³, P(O)R¹³, P⁺R¹³R¹⁴A⁻, phenylene, amino acid, peptide, polypeptide, carbohydrate, polyether, or polyalkyl, and wherein in said polyalkyl, phenylene, amino acid, peptide, polypeptide, and carbohydrate, one or more carbons are optionally replaced by O, NR⁹, N⁺R⁹R¹⁰A—, S, SO, SO₂, S⁺R⁹A—, PR⁹, P⁺R⁹R¹⁰A—, or P(O)R⁹.
 44. The oral pharmaceutical composition of claim 42, wherein said R^(x) is selected from the group consisting of alkyl, aryl, cycloalkyl, heterocycle, polyalkyl, acyloxy, polyether, halogen, OR¹³, NR¹³R¹⁴, NR¹³NR¹⁴R¹⁵, N⁺R⁹R¹¹R¹²A⁻, SR¹³, S⁺R¹³R¹⁴, CO₂R¹³, NR¹⁴C(O)R¹³, and NR¹⁴C(O)R¹³, wherein alkyl, aryl, cycloalkyl, heterocycle, polyalkyl, acyloxy, and polyether, can be further substituted with OR⁹, NR⁹R¹⁰, N⁺R⁹R¹¹R¹²A⁻, SR⁹, S(O)R⁹, SO₂R⁹, SO₃R⁹, oxo, CO₂R⁹, CN, halogen, CONR⁹R¹⁰SO₂OM, SO₂NR⁹R¹⁰, PO(OR¹⁶)OR¹⁷, P⁺R⁹R¹¹R¹²A⁻, S⁺R⁹R¹⁰A⁻, or C(O)OM, and wherein in R^(x), one or more carbons are optionally replaced by O, NR¹³, N⁺R¹³R¹⁴A—, S, SO, SO₂, S⁺R¹³A—, PR¹³, P(O)R¹³, P⁺R¹³R¹⁴A—, phenylene, amino acid, peptide, polypeptide, carbohydrate, polyether, or polyalkyl, and wherein in said polyalkyl, phenylene, amino acid, peptide, polypeptide, and carbohydrate, one or more carbons are optionally replaced by O, NR⁹, N⁺R⁹R¹⁰A—, S, SO, SO₂, S⁺R⁹A—, PR⁹, P⁺R⁹R¹⁰A—, or P(O)R⁹.
 45. The oral pharmaceutical composition of claim 43, wherein said one or more Rx are independently selected from the group consisting of polyether, OR¹³, NR¹³R¹⁴, and N⁺R⁹R¹¹R¹²A⁻.
 46. A compound of the claim 44, wherein said R^(x) is selected from the group consisting of polyether, OR¹³, NR¹³R¹⁴, and N⁺R⁹R¹¹R¹²A⁻.
 47. The oral pharmaceutical composition of claim 45, wherein said one or more Rx are independently selected from the group consisting of OR¹³ and NR¹³R¹⁴.
 48. The oral pharmaceutical composition of claim 46, wherein said R^(x) is independently selected from the group consisting of OR¹³ and NR¹³R¹⁴.
 49. The oral pharmaceutical composition of claim 47, wherein R¹³ and R¹⁴ each methyl.
 50. A compound of the claim 48, wherein R¹³ and R¹⁴ each methyl.
 51. The oral pharmaceutical composition of claim 43, wherein one or more R^(y) are independently in the 3- or the 4-position of the phenyl ring of formula (II).
 52. The oral pharmaceutical composition of claim 44, wherein one or more R^(y) are independently in the 3- or the 4-position of the phenyl ring of formula (II).
 53. The oral pharmaceutical composition of claim 51, wherein t is 1 or
 2. 54. The oral pharmaceutical composition of claim 52, wherein t is 1 or
 2. 55. The oral pharmaceutical composition of claim 53, wherein said one or more R^(y) are independently selected from the group consisting of alkyl, polyether, fluoride, chloride, bromide, iodide, NR¹³R¹⁴, NR¹⁴C(O)R¹³, and OR¹³, wherein alkyl and polyether can be further substituted with SO₃R⁹, N⁺R⁹R¹¹R¹²A⁻, and quaternary heteroaryl.
 56. The oral pharmaceutical composition of claim 54, wherein said R^(y) is independently selected from the group consisting of alkyl, polyether, fluoride, chloride, bromide, iodide, NR¹³R¹⁴, NR¹⁴C(O)R¹³, and OR¹³, wherein alkyl and polyether can be further substituted with SO₃R⁹, N⁺R⁹R¹¹R¹²A⁻, and quaternary heteroaryl.
 57. The oral pharmaceutical composition of claim 55, wherein said one or more R^(y) are independently selected from the group consisting of alkyl, polyether, fluoride, NR¹³R¹⁴, NR¹⁴C(O)R¹³, and OR¹³, wherein alkyl and polyether can be further substituted with SO₃R⁹, N⁺R⁹R¹¹R¹²A⁻, and quaternary heteroaryl.
 58. The oral pharmaceutical composition of claim 56, wherein said R^(y) is independently selected from the group consisting of alkyl, polyether, fluoride, NR¹³R¹⁴, NR¹⁴C(O)R¹³, and OR¹³, wherein alkyl and polyether can be further substituted with SO₃R⁹, N⁺R⁹R¹¹R¹²A⁻, and quaternary heteroaryl.
 59. The oral pharmaceutical composition of claim 57, wherein said R¹³ and R¹⁴ are alkyl, wherein alkyl can be further substituted with SO³R⁹, N⁺R⁹R¹¹R¹²A⁻, and quaternary heteroaryl.
 60. The oral pharmaceutical composition of claim 58, wherein said R⁹ and R¹⁰ are alkyl, wherein alkyl can be further substituted with SO³R⁹, N⁺R⁹R¹¹R¹²A⁻, and quaternary heteroaryl.
 61. The oral pharmaceutical composition of claim 58, wherein n is
 2. 62. The oral pharmaceutical composition of claim 60, wherein n is
 2. 63. The oral pharmaceutical composition of claim 61, wherein said OH group is in a syn relationship to said structure of formula (II).
 64. The oral pharmaceutical composition of claim 62, wherein said OH group is in a syn relationship to said structure of formula (II).
 65. The oral pharmaceutical composition of claim 2 wherein said compound of formula (I) comprises a compound of formula (B-5) represented by:

or an enantiomer, racemate or prodrug thereof and a pharmaceutically acceptable carrier suitable for delivery of said compound of formula (B-5) to the ileum of a mammal by oral administration.
 66. The oral pharmaceutical composition of claim 2, wherein said IBAT inhibitor compound comprises a compound represented by formula (B-5):

or an enantiomer or racemate thereof.
 67. The oral pharmaceutical composition of claim 2, wherein said IBAT inhibitor compound comprises a compound represented by formula (B-5):

or an enantiomer thereof.
 68. The oral pharmaceutical composition of claim 2, wherein said IBAT inhibitor compound comprises a compound represented by formula (B-5):


69. The oral pharmaceutical composition of claim 65 provided in a solid dosage form.
 70. The oral pharmaceutical composition of claim 65 wherein said formula (B-5) is provided in an amount form about 0.1 mg to about 100 mg.
 71. The oral pharmaceutical composition of claim 70 provided in a dosage form selected from the group consisting of a tablet and a capsule, wherein said tablet is optionally coated with an enteric coating.
 72. The oral pharmaceutical composition of claim 71 wherein said enteric coating comprises a coating selected from the group consisting of cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropylmethylcellulose phthalate, and anionic polymers of methacrylic acid and methacrylic acid methyl ester.
 73. The oral pharmaceutical composition of claim 65, wherein said pharmaceutical composition is a pH sensitive release formulation.
 74. The oral pharmaceutical composition of claim 65, wherein said pharmaceutical composition is a bioadhesive formulation.
 75. The oral pharmaceutical composition of claim 65, wherein release of said compound of formula (B-5) is accomplished by enzymatic action.
 76. The oral pharmaceutical composition of claim 2, wherein said formulation is suitable for the treatment of hypercholesterolemia or atherosclerosis.
 77. An oral pharmaceutical composition comprising an ileal bile acid transport (IBAT) inhibitor and a pharmaceutically acceptable carrier, wherein said oral pharmaceutical composition provides delayed release or sustained release of said IBAT inhibitor to the gastrointestinal tract of a subject to whom said composition is administered, and wherein said IBAT inhibitor is represented by a compound of formula (I):

wherein: q is an integer from 1 to 4; n is an integer from 0 to 2; R¹ and R² are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl, wherein alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl optionally are substituted with one or more substituents selected from the group consisting of OR⁹, NR⁹R¹⁰, N⁺R⁹R¹⁰R^(w)A⁻, SR⁹, S⁺R⁹R¹⁰A⁻, P⁺R⁹R¹⁰R¹¹A⁻, S(O)R⁹, SO₂R⁹, SO₃R⁹, CO₂R⁹, CN, halogen, oxo, and CONR⁹R¹⁰, wherein alkyl, alkenyl, alkynyl, alkylaryl, alkoxy, alkoxyalkyl, (polyalkyl)aryl, and cycloalkyl optionally have one or more carbons replaced by O, NR⁹, N⁺R⁹R¹⁰A—, S, SO, SO₂, S⁺R⁹A⁻, P⁺R⁹R¹⁰A⁻, or phenylene, wherein R⁹, R¹⁰, and R^(w) are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, arylalkyl, and alkylammoniumalkyl; or R¹ and R² taken together with the carbon to which they are attached form C₃-C₁₀ cycloalkyl; R³ and R⁴ are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, acyloxy, aryl, heterocycle, OR⁹, NR⁹R¹⁰, SR⁹, S(O)R⁹, SO₂R⁹, and SO₃R⁹, wherein R⁹ and R¹⁰ are as defined above; or R³ and R⁴ together form ═O, ═NOR¹¹, ═S, ═NNR¹¹R¹², ═NR⁹, or ═CR¹¹R¹², wherein R¹¹ and R¹² are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl, OR⁹, NR⁹R¹⁰, SR⁹, S(O)R⁹, SO₂R⁹, SO₃R⁹, CO₂R⁹, CN, halogen, oxo, and CONR⁹R¹⁰, wherein R⁹ and R¹⁰ are as defined above, provided that both R³ and R⁴ cannot be OH, NH₂, and SH, or R¹¹ and R¹² together with the nitrogen or carbon atom to which they are attached form a cyclic ring; R⁵ and R⁶ are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, OR³⁰, SR⁹, S(O)R⁹, SO₂R⁹, and SO₃R⁹, wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, and quaternary heteroaryl can be substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, halogen, oxo, OR¹³, NR¹³R¹⁴, SR¹³, S(O)R¹³, SO₂R¹³, SO₃R¹³, NR¹³OR¹⁴, NR¹³NR¹⁴R¹⁵, NO₂, CO₂R¹³, CN, OM, SO₂OM, SO₂NR¹³R¹⁴, C(O)NR¹³R¹⁴, C(O)OM, COR¹³, P(O)R¹³R¹⁴, P⁺R¹³R¹⁴R¹⁵A⁻, P(OR¹³)OR¹⁴, S⁺R¹³R¹⁴A⁻, and N⁺R⁹R¹¹R¹²A⁻,  wherein: A⁻ is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation, said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can be further substituted with one or more substituent groups selected from the group consisting of OR⁷, NR⁷R⁸, SR⁷, S(O)R⁷, SO₂R⁷, SO₃R⁷, CO₂R⁷, CN, oxo, CONR⁷R⁸, N⁺R⁷R⁸R⁹A—, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, P(O)R⁷R⁸, P⁺R⁷R⁸R⁹A⁻, and P(O)(OR⁷)OR⁸, and wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can optionally have one or more carbons replaced by O, NR⁷, N⁺R⁷R⁸A—, S, SO, SO₂, S⁺R⁷A—, PR⁷, P(O)R⁷, P⁺R⁷R⁸A—, or phenylene, and R¹³, R¹⁴, and R¹⁵ are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, aryl, arylalkyl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, and quaternary heteroarylalkyl, wherein alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, and polyalkyl optionally have one or more carbons replaced by O, NR⁹, N⁺R⁹R¹⁰A—, S, SO, SO₂, S⁺R⁹A⁻, PR⁹, P⁺R⁹R¹⁰A—, P(O)R⁹, phenylene, carbohydrate, amino acid, peptide, or polypeptide, and R¹³, R¹⁴, and R¹⁵ are optionally substituted with one or more groups selected from the group consisting of sulfoalkyl, quaternary heterocycle, quaternary heteroaryl, OR⁹, NR⁹R¹⁰, N⁺R⁹R¹¹R¹²A⁻, SR⁹, S(O)R⁹, SO₂R⁹, SO₃R⁹, oxo, CO₂R⁹, CN, halogen, CONR⁹R¹⁰, SO₂OM, SO₂NR⁹R¹⁰, PO(OR¹⁶)OR¹⁷, P⁺R⁹R¹⁰R¹¹A—, S⁺R⁹R¹⁰A—, and C(O)OM, wherein R¹⁶ and R¹⁷ are independently selected from the substituents constituting R⁹ and M; or R¹⁴ and R¹⁵, together with the nitrogen atom to which they are attached, form a cyclic ring; and R³⁰ is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, alkylammoniumalkyl, and arylalkyl; and R⁷ and R⁸ are independently selected from the group consisting of hydrogen and alkyl; and one or more R^(x) are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, polyalkyl, acyloxy, aryl, arylalkyl, halogen, haloalkyl, cycloalkyl, heterocycle, heteroaryl, polyether, quaternary heterocycle, quaternary heteroaryl, OR¹³, N¹³R¹⁴, SR¹³, S(O)R¹³, S(O)₂R¹³, SO₃R¹³, S⁺R¹³R¹⁴A—, NR¹³OR¹⁴, NR¹³NR¹⁴R¹⁵, NO₂, CO₂R¹³, CN, OM, SO₂OM, SO₂NR¹³R¹⁴, NR¹⁴C(O)R¹³, C(O)NR¹³R¹⁴, NR14C(O)R13, C(O)OM, COR¹³, OR¹⁸, S(O)_(n)NR¹⁸, NR¹³R¹⁸, NR¹⁸OR¹⁴, N⁺R⁹R¹¹R¹²A⁻, P⁺R⁹R¹¹R¹²A⁻, amino acid, peptide, polypeptide, and carbohydrate, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, polyalkyl, heterocycle, acyloxy, arylalkyl, haloalkyl, polyether, quaternary heterocycle, and quaternary heteroaryl can be further substituted with OR⁹, NR⁹R¹⁰, N⁺R⁹R¹¹R¹²A⁻, SR⁹, S(O)R⁹, SO₂R⁹, SO₃R⁹, oxo, CO₂R⁹, CN, halogen, CONR⁹R¹⁰, SO₂OM, SO₂NR⁹R¹⁰, PO(OR¹⁶)OR¹⁷, P⁺R⁹R¹¹R¹²A⁻, S⁺R⁹R¹⁰A⁻, or C(O)OM, and wherein R¹⁸ is selected from the group consisting of acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, wherein acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, quaternary heterocycle, and quaternary heteroaryl optionally are substituted with one or more substituents selected from the group consisting of OR⁹, NR⁹R¹⁰, N⁺R⁹R¹¹R¹²A⁻, SR⁹, S(O)R⁹, SO₂R⁹, SO₃R⁹, oxo, CO₂R⁹, CN, halogen, CONR⁹R¹⁰, SO₃R⁹, SO₂OM, SO₂NR⁹R¹⁰, PO(OR¹⁶)OR¹⁷, and C(O)OM, wherein in R^(x), one or more carbons are optionally replaced by O, NR¹³, N⁺R¹³ R¹⁴A—, S, SO, SO₂, S⁺R¹³A⁻, PR¹³, P(O)R¹³, P⁺R¹³R¹⁴A—, phenylene, amino acid, peptide, polypeptide, carbohydrate, polyether, or polyalkyl, wherein in said polyalkyl, phenylene, amino acid, peptide, polypeptide, and carbohydrate, one or more carbons are optionally replaced by O, NR⁹, N⁺R⁹R¹⁰A⁻, S, SO, SO₂, S⁺R⁹A—, PR⁹, P⁺R⁹R¹⁰A—, or P(O)R⁹; wherein quaternary heterocycle and quaternary heteroaryl are optionally substituted with one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR¹³, NR¹³R¹⁴, SR¹³, S(O)R¹³, SO₂R¹³, SO₃R¹³, NR¹³OR¹⁴, NR¹³NR¹⁴R¹⁵, NO₂, CO₂R¹³, CN, OM, SO₂OM, SO₂NR¹³R¹⁴, C(O)NR¹³R¹⁴, C(O)OM, COR¹³, P(O)R¹³R¹⁴, P⁺R¹³R¹⁴R¹⁵A⁻, P(OR¹³)OR¹⁴, S⁺R¹³R¹⁴A⁻, and N⁺R⁹R¹¹R¹²A⁻, provided that both R⁵ and R⁶ cannot be hydrogen or SH; provided that when R⁵ or R⁶ is phenyl, only one of R¹ or R² is H; provided that when q=1 and R^(x) is styryl, anilido, or anilinocarbonyl, only one of R⁵ or R⁶ is alkyl; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
 78. The oral pharmaceutcal compositon of claim 77, wherein said oral pharmaceutical composition is designed to deliver said IBAT inhibitor to the small intestine of said subject.
 79. The oral pharmaceutical composition of claim 78, wherein said oral pharmaceutical composition is designed to deliver said IBAT inhibitor to the ileum of said subject.
 80. The oral pharmaceutical composition of claim 78, wherein said subject is a human.
 81. The oral pharmaceutical composition of claim 79, wherein said compound of formula (I) comprises a compound represented by formula (B-5):

or an enantiomer, racemate or prodrug thereof.
 82. The oral pharmaceutical composition of claim 79, wherein said compound of formula (I) comprises a compound represented by formula (B-5):

or an enantiomer or racemate thereof.
 83. The oral pharmaceutical composition of claim 79, wherein said compound of formula (I) comprises a compound represented by formula (B-5):

or an enantiomer thereof.
 84. The oral pharmaceutical composition of claim 79, wherein said compound of formula (I) comprises a compound represented by formula (B-5):


85. The oral pharmaceutical composition of claim 83, wherein said oral pharmaceutical composition is provided in a solid dosage form.
 86. The oral pharmaceutical composition of claim 85, wherein said solid dosage form comprises a tablet dosage form.
 87. The oral pharmaceutical composition of claim 85, wherein said solid dosage form comprises a capsule dosage form.
 88. A method for the prophylactic or therapeutic treatment of hypercholesterolemia comprising the step of administering an oral pharmaceutical composition comprising an ileal bile acid transport (IBAT) inhibitor compound and a pharmaceutically acceptable carrier, wherein said IBAT inhibitor compound is represented by formula (I):

wherein: q is an integer from 1 to 4; n is an integer from 0 to 2; R¹ and R² are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl, wherein alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl optionally are substituted with one or more substituents selected from the group consisting of OR⁹, NR⁹R¹⁰, N⁺R⁹R¹⁰R^(w)A⁻, SR⁹, S⁺R⁹R¹⁰A⁻, P⁺R⁹R¹⁰R¹¹A⁻, S(O)R⁹, SO₂R⁹,SO₃R⁹, CO₂R⁹, CN, halogen, oxo, and CONR⁹R¹⁰, wherein alkyl, alkenyl, alkynyl, alkylaryl, alkoxy, alkoxyalkyl, (polyalkyl)aryl, and cycloalkyl optionally have one or more carbons replaced by O, NR⁹, N⁺R⁹R¹⁰A—, S, SO, SO₂, S⁺R⁹A⁻, P⁺R⁹R¹⁰A⁻, or phenylene, wherein R⁹, R¹⁰, and R^(w) are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, anmoniumalkyl, arylalkyl, and alkylammoniumalkyl; or R¹ and R² taken together with the carbon to which they are attached form C₃-C₁₀ cycloalkyl; R³ and R⁴ are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, acyloxy, aryl, heterocycle, OR⁹, NR⁹R¹⁰, SR⁹, S(O)R⁹, SO₂R⁹, and SO₃R⁹, wherein R⁹ and R¹⁰ are as defined above; or R³ and R⁴ together form ═O, ═NOR¹¹, ═S, ═NNR¹¹R¹², ═NR⁹, or ═CR¹¹R¹², wherein R¹¹ and R¹² are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl, OR⁹, NR⁹R¹⁰, SR⁹, S(O)R⁹, SO₂R⁹, SO₃R⁹, CO₂R⁹, CN, halogen, oxo, and CONR⁹R¹⁰, wherein R⁹ and R¹⁰ are as defined above, provided that both R³ and R⁴ cannot be OH, NH₂, and SH, or R¹¹ and R¹² together with the nitrogen or carbon atom to which they are attached form a cyclic ring; R⁵ and R⁶ are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, OR³⁰, SR⁹, S(O)R⁹, SO₂R⁹, and SO₃R⁹, wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, and quaternary heteroaryl can be substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, halogen, oxo, OR¹³, NR¹³R¹⁴, SR¹³, S(O)R¹³, SO₂R¹³, SO₃R¹³, NR¹³OR¹⁴, NR¹³NR¹⁴R¹⁵, NO₂, CO₂R¹³, CN, OM, SO₂OM, SO₂NR¹³R¹⁴, C(O)NR¹³R¹⁴, C(O)OM, COR¹³, P(O)R¹³R¹⁴, P⁺R¹³R¹⁴R¹⁵A⁻, P(OR¹³)OR¹⁴, S⁺R¹³R¹⁴A⁻, and N⁺R⁹R¹¹R¹²A⁻,  wherein: A⁻ is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation, said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can be further substituted with one or more substituent groups selected from the group consisting of OR⁷, NR⁷R⁸, SR⁷, S(O)R⁷, SO₂R⁷, SO₃R⁷, CO₂R⁷, CN, oxo, CONR⁷R⁸, N⁺R⁷R⁸R⁹A—, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, P(O)R⁷R⁸, P⁺R⁷R⁸R⁹A⁻, and P(O)(OR⁷)OR⁸, and wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can optionally have one or more carbons replaced by O, NR⁷, N⁺R⁷R⁸A—, S, SO, SO₂, S⁺R⁷A—, PR⁷, P(O)R⁷, P⁺R⁷R⁸A—, or phenylene, and R¹³, R¹⁴, and R¹⁵ are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, aryl, arylalkyl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, and quaternary heteroarylalkyl, wherein alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, and polyalkyl optionally have one or more carbons replaced by O, NR⁹, N⁺R⁹R¹⁰A—, S, SO, SO₂, S⁺R⁹A⁻, PR⁹, P⁺R⁹R¹⁰A—, P(O)R⁹, phenylene, carbohydrate, amino acid, peptide, or polypeptide, and R¹³, R¹⁴, and R¹⁵ are optionally substituted with one or more groups selected from the group consisting of sulfoalkyl, quaternary heterocycle, quaternary heteroaryl, OR⁹, NR⁹R¹⁰, N⁺R⁹R¹¹R¹²A⁻, SR⁹, S(O)R⁹, SO₂R⁹, SO₃R⁹, oxo, CO₂R⁹, CN, halogen, CONR⁹R¹⁰, SO₂OM, SO₂NR⁹R¹⁰, PO(OR¹⁶)OR¹⁷, P⁺R⁹R¹⁰R¹¹A—, S⁺R⁹R¹⁰A—, and C(O)OM, wherein R¹⁶ and R¹⁷ are independently selected from the substituents constituting R⁹ and M; or R¹⁴ and R¹⁵, together with the nitrogen atom to which they are attached, form a cyclic ring; and R³⁰ is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, alkylammoniumalkyl, and arylalkyl; and R⁷ and R⁸ are independently selected from the group consisting of hydrogen and alkyl; and one or more R^(x) are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, polyalkyl, acyloxy, aryl, arylalkyl, halogen, haloalkyl, cycloalkyl, heterocycle, heteroaryl, polyether, quaternary heterocycle, quaternary heteroaryl, OR¹³, NR¹³R¹⁴, SR¹³, S(O)R¹³, S(O)₂R¹³, SO₃R¹³, S⁺R¹³R¹⁴A—, NR¹³OR¹⁴, NR¹³NR¹⁴R¹⁵, NO₂, CO₂R¹³, CN, OM, SO₂OM, SO₂NR¹³R¹⁴, NR¹⁴C(O)R¹³, C(O)NR¹³R¹⁴, NR14C(O)R13, C(O)OM, COR¹³, OR¹⁸, S(O)_(n)NR¹⁸, NR¹³R¹⁸, NR¹⁸OR¹⁴, N⁺R⁹R¹¹R¹²A⁻, P⁺R⁹R¹¹R¹²A⁻, amino acid, peptide, polypeptide, and carbohydrate, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, polyalkyl, heterocycle, acyloxy, arylalkyl, haloalkyl, polyether, quaternary heterocycle, and quaternary heteroaryl can be further substituted with OR⁹, NR⁹R¹⁰, N⁺R⁹R¹¹R¹²A⁻, SR⁹, S(O)R⁹, SO₂R⁹, SO₃R⁹, oxo, CO₂R⁹, CN, halogen, CONR⁹R¹⁰, SO₂OM, SO₂NR⁹R¹⁰, PO(OR¹⁶)OR¹⁷, P⁺R⁹R¹¹R¹²A⁻, S⁺R⁹R¹⁰A⁻, or C(O)OM, and wherein R¹⁸ is selected from the group consisting of acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, wherein acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, quaternary heterocycle, and quaternary heteroaryl optionally are substituted with one or more substituents selected from the group consisting of OR⁹, NR⁹R¹⁰, N⁺R⁹R¹¹R¹²A⁻, SR⁹, S(O)R⁹, SO₂R⁹, SO₃R⁹, oxo, CO₂R⁹, CN, halogen, CONR⁹R¹⁰, SO₃R⁹, SO₂OM, SO₂NR⁹R¹⁰, PO(OR¹⁶)OR¹⁷, and C(O)OM, wherein in R^(x), one or more carbons are optionally replaced by O, NR¹³, N⁺R¹³R¹⁴A—, S, SO, SO₂, S⁺R¹³A⁻, PR¹³, P(O)R¹³, P⁺R¹³R¹⁴A—, phenylene, amino acid, peptide, polypeptide, carbohydrate, polyether, or polyalkyl, wherein in said polyalkyl, phenylene, amino acid, peptide, polypeptide, and carbohydrate, one or more carbons are optionally replaced by O, NR⁹, N⁺R⁹R¹⁰A⁻, S, SO, SO₂, S⁺R⁹A—, PR⁹, P⁺R⁹R¹⁰A—, or P(O)R⁹; wherein quaternary heterocycle and quaternary heteroaryl are optionally substituted with one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR¹³, NR¹³R¹⁴, SR¹³, S(O)R¹³, SO₂R¹³, SO₃R¹³, NR¹³OR¹⁴, NR¹³NR¹⁴R¹⁵, NO₂, CO₂R¹³, CN, OM, SO₂OM, SO₂NR¹³R¹⁴, C(O)NR¹³R¹⁴, C(O)OM, COR¹³, P(O)R¹³R¹⁴, P⁺R¹³R¹⁴R¹⁵A⁻, P(OR¹³)OR¹⁴, S⁺R¹³R¹⁴A⁻, and N⁺R⁹R¹¹R¹²A⁻, provided that both R⁵ and R⁶ cannot be hydrogen or SH; provided that when R⁵ or R⁶ is phenyl, only one of R¹ or R² is H; provided that when q=1 and R^(x) is styryl, anilido, or anilinocarbonyl, only one of R⁵ or R⁶ is alkyl; or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and wherein said oral pharmaceutical composition is suitable for delivery of said compound of formula (I) to the small intestine by oral administration.
 89. The method of claim 88, wherein said oral pharmaceutical composition is suitable for delivery of said compound of formula (I) to the ileum by oral administration.
 90. The method of claim 89, wherein said IBAT inhibitor compound comprises a compound represented by formula (B-5):

or an enantiomer, racemate or prodrug thereof.
 91. The method of claim 89, wherein said IBAT inhibitor compound comprises a compound represented by formula (B-5):

or an enantiomer or racemate thereof.
 92. The method of claim 89, wherein said IBAT inhibitor compound comprises a compound represented by formula (B-5):

or an enantiomer thereof.
 93. The method of claim 89, wherein said IBAT inhibitor compound comprises a compound represented by formula (B-5): 